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Abstract:

Some embodiments of the present invention provide stimulation systems and
components for selective stimulation and/or neuromodulation of one or
more dorsal root ganglia through implantation of an electrode on, in or
around a dorsal root ganglia. Some other embodiments of the present
invention provide methods for selective neurostimulation of one or more
dorsal root ganglia as well as techniques for applying neurostimulation
to the spinal cord. Still other embodiments of the present invention
provide stimulation systems and components for selective stimulation
and/or neuromodulation of one or more dorsal root ganglia through
implantation of an electrode on, in or around a dorsal root ganglia in
combination with a pharmacological agent.

Claims:

1. A method of stimulating a dorsal root ganglion of a patient,
comprising: implanting at least one electrode in proximity to the dorsal
root; and activating the at least one electrode to selectively stimulate
at least a portion of the dorsal root ganglion to create paresthesia in
an area of the patient's body.

2. A method as in claim 1, wherein activating the at least one electrode
to selectively stimulate comprises providing stimulation energy below a
threshold for stimulating a ventral root associated with the dorsal root
ganglion.

3. A method as in claim 1, wherein activating the at least one electrode
to selectively stimulate comprises providing a stimulation energy that
stimulates sensory nerves without stimulating motor nerves.

4. A method as in claim 1, wherein activating the at least one electrode
to selectively stimulate comprises providing a stimulation energy which
preferentially stimulates myelinated fibers over unmyelinated fibers.

5. A method as in claim 1, wherein intensity and/or distribution of the
paresthesia lacks clinically significant changes during movement of the
patient.

6. A method as in claim 5, wherein movement of the patient comprises
movement of the patient from an upright position to a recumbant position
or vice versa.

7. A method as in claim 5, wherein movement of the patient comprises
flexion, extension or rotation of a portion of a spine of the patient.

8. A method as in claim 5, wherein the lack of clinically significant
changes during movement of the patient is due to anchoring of the
electrode in position by an anchor.

9. A method as in claim 5, wherein the lack of clinically significant
changes during movement of the patient is achieved without the use of an
anchor.

10. A method of stimulating a dorsal root ganglion of a patient,
comprising: implanting at least one electrode in proximity to the dorsal
root ganglion so that the at least one electrode maintains its position
in proximity to the dorsal root ganglion throughout a body position
change of the patient; and activating the at least one electrode to
selectively stimulate at least a portion of the dorsal root ganglion.

11. A method as in claim 10, wherein activating the at least one
electrode to selectively stimulate comprises providing stimulation energy
below a threshold for stimulating a ventral root associated with the
dorsal root ganglion.

12. A method as in claim 10, wherein activating the at least one
electrode to selectively stimulate comprises providing a stimulation
energy that stimulates sensory nerves without stimulating motor nerves.

13. A method as in claim 10, wherein activating the at least one
electrode to selectively stimulate comprises providing a stimulation
energy which preferentially stimulates myelinated fibers over
unmyelinated fibers.

14. A method as in claim 10, wherein the body position change of the
patient comprises moving to a recumbant position from an upright position
or vice versa.

15. A method as in claim 10, wherein the body position change of the
patient comprises flexion, extension or rotation of a portion of a spine
of the patient.

16. A method as in claim 10, wherein maintaining position of the at least
one electrode maintains intensity of paresthesia.

17. A method as in claim 10, wherein maintaining position of the at least
one electrode maintains distribution of paresthesia.

18. A method as in claim 10, wherein maintaining position of the at least
one electrode maintains intensity and distribution of paresthesia.

19. A method as in claim 10, wherein the at least one electrode maintains
its position due to anchoring by an anchor.

20. A method as in claim 10, wherein the at least one electrode maintains
its position without the use of an anchor.

[0002] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same extent as
if each individual publication or patent application was specifically and
individually indicated to be incorporated by reference.

FIELD

[0003] The present invention relates to neurostimulation methods and
systems that enable more precise stimulation of the nervous system. In
particular, embodiments of the present invention provide for the
controlled stimulation of spinal and paraspinal nerve root ganglion. In
one embodiment, the ganglion is a dorsal root ganglion (DRG) and in
another embodiment the ganglion is part of the sympathetic nervous
system.

BACKGROUND

[0004] Application of specific electrical energy to the spinal cord for
the purpose of managing pain has been actively practiced since the 1960s.
While a precise understanding of the interaction between the applied
electrical energy and the nervous tissue is not fully appreciated, it is
known that application of an electrical field to spinal nervous tissue
can effectively mask certain types of pain transmitted from regions of
the body associated with the stimulated nervous tissue. More
specifically, applying particularized electrical pulses to the spinal
cord associated with regions of the body afflicted with chronic pain can
induce paresthesia, or a subjective sensation of numbness or tingling, in
the afflicted bodily regions. This paresthesia can effectively inhibit
the transmission of non-acute pain sensations to the brain.

[0005] Electrical energy, similar to that used to inhibit pain perception,
may also be used to manage the symptoms of various motor disorders, for
example, tremor, dystonia, spasticity, and the like. Motor spinal nervous
tissue, or nervous tissue from ventral nerve roots, transmits
muscle/motor control signals. Sensory spinal nervous tissue, or nervous
tissue from dorsal nerve roots, transmit pain signals. Corresponding
dorsal and ventral nerve roots depart the spinal cord "separately";
however, immediately thereafter, the nervous tissue of the dorsal and
ventral nerve roots are mixed, or intertwined. Accordingly, electrical
stimulation intended to manage/control one condition (for example, pain)
often results in the inadvertent interference with nerve transmission
pathways in adjacent nervous tissue (for example, motor nerves).

[0006] As illustrated in FIG. 1, prior art spinal column or spinal cord
stimulators (SCS) commonly deliver electrical energy to the spinal cord
through an elongate paddle 5 or epidural electrode array containing
electrodes 6 positioned external to the spinal cord dura layer 32. The
spinal cord dura layer 32 surrounds the spinal cord 13 and is filled with
cerebral spinal fluid (CSF). The spinal cord 13 is a continuous body and
three spinal levels 14 of the spinal cord 13 are illustrated. For
purposes of illustration, spinal levels 14 are sub-sections of the spinal
cord 13 depicting that portion where the dorsal and ventral roots join
the spinal cord 13. The peripheral nerve 44 divides into the dorsal root
42 and dorsal root ganglion 40 and the ventral nerve root 41 each of
which feed into the spinal cord 13. An ascending pathway 92 is
illustrated between level 2 and level 1 and a descending pathway 94 is
illustrated from level 2 to level 3. Spinal levels 14 can correspond to
the vertebral levels of the spine commonly used to describe the vertebral
bodies of the spine. For simplicity, each level illustrates the nerves of
only one side and a normal anatomical configuration would have similar
nerves illustrated in the side of the spinal cord 13 directly adjacent
the paddle 5.

[0007] Typically, SCS are placed in the spinal epidural space.
Conventional SCS systems are described in numerous patents. Additional
details of the placement and use of SCS can be found, for example, in
U.S. Pat. No. 6,319,241 which is incorporated herein by reference in its
entirety. In general, the paddle 5 is about 8 mm wide and from 24 to 60
mm long depending upon how many spinal levels are stimulated. The
illustrated electrode paddle 5 is adapted to conventionally stimulate all
three spinal levels 14. These exemplary levels 1, 2 and 3 could be
anywhere along the spinal cord 13. Positioning a stimulation paddle 5 in
this manner results in the electrodes 6 spanning a plurality of nerves,
here the dorsal root ganglion 40, the ventral root 41 and peripheral
nerve 41 on multiple spinal levels.

[0008] Because the paddle 5 spans several levels the generated stimulation
energy 8 stimulates or is applied to more than one type of nerve tissue
on more than one level. Moreover, these and other conventional,
non-specific stimulation systems also apply stimulation energy to the
spinal cord and to other neural tissue beyond the intended stimulation
targets. As used herein, non-specific stimulation refers to the fact that
the stimulation energy is provided to all spinal levels including the
nerves and the spinal cord generally and indiscriminately. Even if the
epidural electrode is reduced in size to simply stimulate only one level,
that electrode will apply stimulation energy indiscriminately to
everything (i.e., all nerve fibers and other tissues) within the range of
the applied energy 8. Moreover, larger epidural electrode arrays may
alter cerebral spinal fluid (CSF) flow thus further altering local neural
excitability states.

[0009] Another challenge confronting conventional neuro stimulation
systems is that since epidural electrodes must apply energy across a wide
variety of tissues and fluids (i.e., CSF fluid amount varies along the
spine as does pia matter thickness) the amount of stimulation energy
needed to provide the desired amount of neurostimulation is difficult to
precisely control. As such, increasing amounts of energy may be required
to ensure sufficient stimulation energy reaches the desired stimulation
area. However, as applied stimulation energy increases so too increases
the likelihood of deleterious damage or stimulation of surrounding
tissue, structures or neural pathways.

[0010] To achieve stimulation the targeted tissue, the applied electrical
energy should be properly defined and undesired energy application to
non-targeted tissue be reduced or avoided. An improperly defined electric
field may not only be ineffective in controlling/managing the desired
condition(s) but may also inadvertently interfere with the proper neural
pathways of adjacent spinal nervous tissue. Accordingly, a need exists
for stimulation methods and systems that enable more precise delivery of
stimulation energy.

SUMMARY OF THE DISCLOSURE

[0011] In one embodiment, there is provided a method of stimulating a
dorsal root ganglion by implanting an electrode in proximity to the
dorsal root ganglion; and activating the electrode to stimulate a portion
of the dorsal root ganglion, or activating the electrode to stimulate
substantially only the dorsal root ganglion.

[0012] In another embodiment, there is provided a method of stimulating a
nerve root ganglion by implanting an electrode into the nerve root
ganglion; and activating the electrode to stimulate the nerve root
ganglion.

[0013] In another embodiment, there is provided, a method of stimulating
the spinal cord by implanting an electrode into the spinal cord; and
providing stimulation energy to spinal cord fibers using the electrode.

[0014] In another embodiment, there is provided a method of modulating
nervous tissue within a dorsal root ganglion by implanting an electrode
within a dorsal root ganglion; and providing electrical stimulation from
the electrode to stimulate neural tissue within the dorsal root ganglion.

[0015] In another embodiment, there is provided a method of modulating a
neural pathway in the sympathetic nervous system by stimulating a spinal
dorsal root ganglion upstream of at least one ganglion of the sympathetic
nerve chain to influence a condition associated with the at least one
ganglion of the sympathetic nerve chain.

[0016] In yet another embodiment, there is provided a neurostimulation
system having an electrode adapted for stimulation of only a nerve root
ganglion; a signal generator coupled to the electrode; and a controller
to control the output of the signal generator.

[0017] In yet another embodiment, there is provided a method of
stimulating the spinal cord by piercing the spinal dura matter; and
placing an electrode into contact with a portion of the intra-madullary
of the spinal cord.

[0018] In yet another embodiment, there is a method of stimulating the
nervous system by implanting an electrode such that when the electrode is
activated, the electrode stimulates only a nerve root ganglion.

[0019] In yet another embodiment, there is provided a method of
stimulating neural tissue to treat a condition including stimulating an
electrode implanted to stimulate only a dorsal root ganglion on a spinal
level wherein the stimulation treats the condition.

[0020] In yet another embodiment, there is provided a stimulation
component, comprising a proximal connector; a distal electrode configured
to be implanted within the body at a stimulation site; an electrical lead
connected to the proximal connector and the distal electrode; a strain
relief mechanism in proximity to the stimulation site; and a fixation
element adapted to reduce the amount of movement of the electrical lead
proximal to a fixation point in an anatomical structure proximal to the
stimulation site. In one aspect, an electrode maintains its position
using a strain relief when the stimulation site is a dorsal root
ganglion.

[0021] In another embodiment, there is provided a stimulation component,
comprising a proximal connector; a distal electrode configured to be
implanted within the body at a stimulation site; an electrical lead
connected to the proximal connector and the distal electrode; a strain
relief mechanism in proximity to the stimulation site; and a fixation
element adapted to reduce the amount of movement of the electrical lead
proximal to a fixation point in an anatomical structure proximal to the
stimulation site. In one aspect, an electrode maintains its position
using a fixation element when the stimulation site is a dorsal root
ganglion.

[0022] In yet another embodiment, there is provided a neurostimulation
component, comprising a body having a distal end and a proximal end and a
length selected to implant the body within a targeted neural tissue; a
tip on the distal end of the body adapted to anchor in proximity to the
targeted neural tissue; and an electrode structure positioned on the body
adapted to neurostimulate only the targeted neural tissue.

[0023] In yet another embodiment, there is provided a method of
neurostimulating targeted neural tissue, comprising implanting an
electrode in a position adapted to neurostimulate only targeted neural
tissue; and providing a controlled stimulation signal from a signal
generator coupled to the electrode.

[0024] In one embodiment, a method of stimulating a dorsal root ganglion
of a patient is provided, wherein the method includes implanting at least
one electrode in proximity to the dorsal root and activating the at least
one electrode to selectively stimulate at least a portion of the dorsal
root ganglion to create paresthesia in an area of the patient's body. In
some instances, activating the at least one electrode to selectively
stimulate includes providing stimulation energy below a threshold for
stimulating a ventral root associated with the dorsal root ganglion. In
another other instances, activating the at least one electrode to
selectively stimulate includes providing a stimulation energy that
stimulates sensory nerves without stimulating motor nerves. In still
another instances, activating the at least one electrode to selectively
stimulate includes providing a stimulation energy which preferentially
stimulates myelinated fibers over unmyelinated fibers.

[0025] In some embodiments, intensity and/or distribution of the
paresthesia lacks clinically significant changes during movement of the
patient. For example, movement of the patient can include movement of the
patient from an upright position to a recumbant position or vice versa.
Additionally or alternatively, movement of the patient can include
flexion, extension or rotation of a portion of a spine of the patient. It
may be appreciated that the lack of clinically significant changes during
movement of the patient can be due to anchoring of the electrode in
position by an anchor. Or, the lack of clinically significant changes
during movement of the patient can be achieved without the use of an
anchor.

[0026] In one embodiment, a method of stimulating a dorsal root ganglion
of a patient includes implanting at least one electrode in proximity to
the dorsal root ganglion so that the at least one electrode maintains its
position in proximity to the dorsal root ganglion throughout a body
position change of the patient and activating the at least one electrode
to selectively stimulate at least a portion of the dorsal root ganglion.

[0027] In some instances, activating the at least one electrode to
selectively stimulate can include providing stimulation energy below a
threshold for stimulating a ventral root associated with the dorsal root
ganglion. In other instances, activating the at least one electrode to
selectively stimulate includes providing a stimulation energy that
stimulates sensory nerves without stimulating motor nerves. In still
other instances, activating the at least one electrode to selectively
stimulate includes providing a stimulation energy which preferentially
stimulates myelinated fibers over unmyelinated fibers. In some
embodiments, the body position change of the patient includes moving to a
recumbant position from an upright position or vice versa. Additionally
or alternatively, the body position change of the patient can include
flexion, extension or rotation of a portion of a spine of the patient.
Maintaining position of the at least one electrode can maintain intensity
of paresthesia. Likewise, maintaining position of the at least one
electrode can maintain distribution of paresthesia. Thus, maintaining
position of the at least one electrode can maintain intensity and
distribution of paresthesia. In one embodiment, the at least one
electrode can maintain its position due to anchoring by an anchor. In
still another embodiment, the at least one electrode can maintain its
position without the use of an anchor.

BRIEF DESCRIPTION OF THE DRAWINGS

[0028] A better understanding of the features and advantages of the
various embodiments of the present invention will be obtained by
reference to the following detailed description and the accompanying
drawings of which:

[0029] FIG. 1 illustrates a conventional epidural electrode array
positioned external to and stimulating a portion of the spinal cord;

[0038] FIG. 6A illustrates a two electrode, single level activation
pattern and FIG. 6B illustrates an exemplary corresponding dermatome to
the stimulation pattern of FIG. 6A;

[0039] FIG. 7A illustrates a single electrode level and a two electrode
level activation pattern and FIG. 7B illustrates an exemplary
corresponding dermatome to the stimulation pattern of FIG. 7A;

[0040] FIG. 8A is a section view of a spinal level with an electrode being
implanted into a dorsal root ganglia and FIG. 8B is the view of FIG. 8A
with the delivery catheter being withdrawn and the electrode implanted
into the dorsal root ganglia;

[0041] FIG. 9A is a section view of a spinal level with an electrode being
implanted into a dorsal root ganglia using an approach that crosses a
medial line of the level of interest and FIG. 9B is an enlarged view of
the DRG in FIG. 9A with an implanted electrode;

[0042] FIG. 10A is a section view of a spinal level with an electrode
being implanted onto or in the nerve root epinurium using an approach
that crosses a medial line of the level of interest and FIG. 10B is an
enlarged view of the implanted electrode in FIG. 10A;

[0043]FIG. 11 is a illustrates an alternative DRG implantation technique
using an approach along the peripheral nerve;

[0044]FIG. 12A illustrates an implantation technique using an electrode
and anchor design illustrated in FIG. 12B;

[0068]FIG. 33 is an illustration of a portion of sympathetic nervous
system neuromodulated by an stimulation system embodiment of the present
invention;

[0069] FIG. 34 is an illustration of embodiments of the present invention
implanted for the direct stimulation of a single sympathetic nerve
ganglion and a single dorsal root ganglion on the same spinal level;

[0070]FIG. 35 is an illustration of an embodiment of the present
invention implanted for the direct stimulation of the spinal cord;

[0071] FIG. 36 is an illustration of two embodiments of the present
invention implanted for the direct stimulation of the spinal cord;

[0072] FIGS. 37A-37C illustrate sealing embodiments used when implanting
electrodes into the spinal cord; and

[0073]FIG. 38 summarizes numerous alternative embodiments of the
stimulation system of the present invention as applied to different
portions of the spine and dorsal root ganglion.

[0074] FIGS. 39A-39B illustrate, respectively, the paresthesia intensity
scales used by a patient to rate the intensity of paresthesia perceived
from stimulation energy applied while standing up and lying down.

[0075] FIG. 40 is an example of data compiled for a given patient
comparing stimulation level (current amplitude) and paresthesia intensity
while the patient is in a particular body position.

[0077]FIG. 42 is a line graph illustrating the maintenance of paresthesia
intensity over time.

[0078] FIGS. 43A-B are body maps illustrating areas in the patient body
with shaded areas to indicate where paresthesia is felt while in an
upright position and in a supine position, respectively.

DETAILED DESCRIPTION

[0079] Embodiments of the present invention provide novel stimulation
systems and methods that enable direct and specific neurostimulation
techniques. For example, there is provided a method of stimulating a
nerve root ganglion comprising implanting an electrode into the nerve
root ganglion and activating the electrode to stimulate the nerve root
ganglion. As discussed in greater detail below, the nerve root ganglion
may be a dorsal root ganglion in some embodiments while in other
embodiments the nerve root ganglion may be a nerve root ganglion in the
sympathetic nervous system or other ganglion or tissue. In some
embodiments, implanting the electrode includes forming an opening in the
epinurium of the root ganglion and passing the electrode through the
opening and into the interior space or interfascicular space of the
ganglion.

[0080] In other embodiments, portions of an electrode body pass completely
through a ganglion while maintaining an active electrode area
appropriately positioned to deliver stimulation energy to the ganglion.
In still other embodiments of the microelectrodes and stimulation systems
of the invention, the size, shape and position of a microelectrode and
the stimulation pattern or algorithm is chosen to stimulated targeted
neural tissue and exclude others. In other additional embodiments, the
electrode stimulation energy is delivered to the targeted neural tissue
so that the energy dissipates or attenuates beyond the targeted tissue or
region.

[0081] Once the electrode is in place on, in or adjacent the desired nerve
root ganglion, the activating step proceeds by coupling a programmable
electrical signal to the electrode. In one embodiment, the amount of
stimulation energy provided into the nerve ganglion is sufficient to
selectively stimulate neural tissue. In a specific embodiment, the
stimulation energy provided only stimulates neural tissue within the
targeted DRG. Alternatively, the stimulation energy beyond the DRG is
below a level sufficient to stimulate, modulate or influence nearby
neural tissue.

[0082] In an example where the electrode is implanted into a dorsal root
ganglion, the stimulation level may be selected as one that
preferentially activates myelinated, large diameter fibers (such as
Aβ and Aα fibers) over unmyelinated, small diameter fibers
(such as c-fibers). In additional embodiments, the stimulation energy
used to activate an electrode to stimulate neural tissue remains at an
energy level below the level to used ablate, lesion or otherwise damage
the neural tissue. For example, during a radiofrequency percutaneous
partial rhizotomy, an electrode is placed into a dorsal root ganglia and
activated until a thermolesion is formed (i.e., at a electrode tip
temperature of about 67° C.) resulting in a partial and temporary
sensory loss in the corresponding dermatome. In one embodiment, the
stimulation energy levels applied to a DRG remain below the energy levels
used during thermal ablation, RF ablation or other rhizotomy procedures.

[0083] Tissue stimulation is mediated when current flow through the tissue
reaches a threshold, which causes cells experiencing this current flow to
depolarize. Current is generated when a voltage is supplied, for example,
between two electrodes with specific surface area. The current density in
the immediate vicinity of the stimulating electrode is an important
parameter. For example, a current of 1 mA flowing through a 1 mm2
area electrode has the same current density in its vicinity as 10 mA of
current flowing through a 10 mm2 area electrode, that is 1
mA/mm2. In this example, cells close to the electrode surface
experience the same stimulation current. The difference is that the
larger electrode can stimulate a larger volume of cells and the smaller
electrode can stimulate a smaller volume of cells in proportion to their
surface area.

[0084] In many instances, the preferred effect is to stimulate or
reversibly block nervous tissue. Use of the term "block" or "blockade" in
this application means disruption, modulation, and inhibition of nerve
impulse transmission. Abnormal regulation can result in an excitation of
the pathways or a loss of inhibition of the pathways, with the net result
being an increased perception or response. Therapeutic measures can be
directed towards either blocking the transmission of signals or
stimulating inhibitory feedback. Electrical stimulation permits such
stimulation of the target neural structures and, equally importantly,
prevents the total destruction of the nervous system. Additionally,
electrical stimulation parameters can be adjusted so that benefits are
maximized and side effects are minimized.

[0085]FIG. 2A illustrates an embodiment of a stimulation system 100 of
the present invention in place with an electrode 115 implanted into a
spinal dorsal root ganglion 40. For purposes of illustration, spinal
level 14, a sub-section of the spinal cord 13, is used to depict where
the dorsal root 42 and ventral root 41 join the spinal cord 13, indicated
by 42H and 41H respectively. The peripheral nerve 44 divides into the
dorsal root 42 and dorsal root ganglion 40 and the ventral nerve root 41.
For simplicity, the nerves of only one side are illustrated and a normal
anatomical configuration would have similar nerves positioned on the
other side. The spinal dura layer 32 surrounds the spinal cord 13 and is
filled with cerebral spinal fluid (CSF). For clarity, the spinal dura
layer or dura mater 32 alone is used to represent the three spinal
meninges--the pia mater, the arachnoid mater and the dura mater--that
surround and protect the spinal cord 13.

[0086] Note that the electrode 115 is implanted medial to the peripheral
nerve 44 after the nerve root splits into the ventral nerve 41 containing
the motor nerves and the dorsal root 42 containing the sensory nerves.
The electrode 115 is also implanted lateral of the dura layer 32. The
advantageous placement of one or more electrode embodiments of the
present invention enables selective stimulation of neural tissue, such as
a nerve root ganglion, without stimulation of surrounding neural tissue.
In this example, a dorsal root ganglion 40 is stimulated with little or
imperceptible amounts of stimulation energy provided to the motor nerves
within the ventral nerve root 44, portions of the spinal cord 13, spinal
level 14, or the peripheral nerve 44. Embodiments of the present
invention are particularly well suited for providing pain control since
the sensory fibers running through the dorsal root ganglion 40 may be
specifically targeted. Advantageously, embodiments of the present
invention may neuromodulate one or more the dorsal root ganglia for pain
control without influencing surrounding tissue.

[0087] The stimulation system 100 includes a pulse generator that provides
stimulation energy in programmable patterns adapted for direct
stimulation of neural tissue using small area, high impedance
microelectrodes. The level of stimulation provided is selected to
preferentially stimulate the Aβ and Aα fibers 52 over the
c-fibers 54. Stimulation energy levels used by embodiments of the present
invention utilize lower stimulation energy levels than conventional
non-direct, non-specific stimulations systems because the electrode 115
is advantageously placed on, in or about a dorsal root ganglion 40. Based
on conventional gate control theory, it is believed that by stimulating
of the faster transmitting Aβ and Aα fibers 52 by the
stimulation methods of the present invention, the signal 53 from the
fibers 52 will release opiates at the junction of the dorsal root 42 and
the spinal cord 13. This release raises the response threshold at that
junction (elevated junction threshold 56). The later arriving c-fiber
signal 55 remains below the elevated junction threshold 56 and goes
undetected.

[0088] Accordingly, some embodiments of the present invention provide
selective stimulation of the spinal cord, peripheral nervous system
and/or one or more dorsal root ganglia. As used herein in one embodiment,
selective stimulation means that the stimulation substantially only
neuromodulates or neurostimulates a nerve root ganglion. In one
embodiment, selective stimulation of a dorsal root ganglion leaves the
motor nerves unstimulated or unmodulated. In addition, in other
embodiments, selective stimulation can also mean that within the nerve
sheath, the A-myelinated fibers are preferentially stimulated or
neuromodulated as compared to the c-unmyelinated fibers. As such,
embodiments of the present invention advantageously utilize the fact that
A-fibers carry neural impulses more rapidly (almost twice as fast) as
c-fibers. Some embodiments of the present invention are adapted to
provide stimulation levels intended to preferentially stimulate A-fibers
over c-fibers.

[0089] In additional embodiments, selective stimulation can also mean that
the electrode (including an electrode coated with or adapted to deliver a
pharmacological agent, e.g., FIGS. 21, 23A, C and D) is in intimate
contact with the tissue or other nervous system component that is the
subject of stimulation. This aspect recognizes our advantageous use of
electrode placement. In specific illustrative embodiments discussed
further below, one or more stimulation electrodes are placed (1) against
or in contact with the outer sheath of a nerve root ganglion; (2) within
a nerve root ganglion; (3) within the root ganglion interfascicular
space; (4) in contact with a portion of the spinal cord; (5) in a
position that requires piercing of the epidural space, the dura, nerve
root epinurium or a portion of the spinal cord; (6) in contact with a
portion of the sympathetic nervous system or (7) in contact with neural
tissue targeted for direct stimulation.

[0090] Moreover, selective stimulation or neuromodulation concepts
described herein may be applied in a number of different configurations.
Unilateral (on or in one root ganglion on a level), bi-lateral (on or in
two root ganglion on the same level), unilevel (one or more root ganglion
on the same level) or multi-level (at least one root ganglion is
stimulated on each of two or more levels) or combinations of the above
including stimulation of a portion of the sympathetic nervous system and
one or more dorsal root ganglia associated with the neural activity or
transmission of that portion of the sympathetic nervous system. As such,
embodiments of the present invention may be used to create a wide variety
of stimulation control schemes, individually or overlapping, to create
and provide zones of treatment.

[0091]FIG. 3A illustrates an embodiment of a stimulation system 100 of
the present invention with an electrode 115 implanted into a dorsal root
ganglion (DRG) 40. The figure illustrates three representative spinal
levels 14 (i.e., spinal levels 1-3) of the spinal cord 13. The peripheral
nerve 44 feeds into the dorsal root ganglion 40 and the ventral nerve
root 41 each of which feed into the spinal cord 13. The dorsal horns 37,
36 are also indicated. For clarity, the dura 32 and complete spinal cord
13 are not illustrated but are present as described elsewhere in this
application and as occur in human anatomy. These exemplary levels 1, 2
and 3 could be anywhere along the spinal cord 13. For simplicity, each
level illustrates the nerves of only one side.

[0092] Using level 2 as a reference, an ascending pathway 92 is
illustrated between level 2 and level 1 and a descending pathway 94 is
illustrated from level 2 to level 3. Application of stimulation energy or
signals to the DRG 40 in level 2 may be used to block signals progressing
upstream from level 2 towards the path/pathways 92. Moreover, modulation
applied to portions of level 2 but may also be used to effectively block
the neuron paths/pathways from another level (here, alternatively using
levels 1 and/or 3) from reaching the brain. As such, application of
stimulation to the level 2 DRG 40 using an embodiment of an apparatus
and/or method of the present invention may advantageously provide an
effective block of intrasegment pain pathways as well. It is to be
appreciated that while three continuous levels are illustrated, some
embodiments of the present invention may be used to stimulate 2 or more
adjacent levels and still other embodiments may be used to stimulate 2 or
more non-adjacent levels, or combinations thereof.

[0093]FIG. 3B relates the spinal nerve roots to their respective
vertebral spinal levels. The letter C designates nerves and vertebrae in
the cervical levels. The letter T designates vertebrae and nerves in the
thoracic levels. The letter L designates vertebrae and nerves in the
lumbar levels. The letter S designates vertebrae and nerves in the sacral
levels. FIG. 3c illustrates the various dermatomes of the body related to
their respective nerve roots using the designations in FIG. 3B.

[0094] FIGS. 4-7 illustrate one embodiment of a stimulation system
activated under a variety of control conditions to provide different
levels and degrees of pain control. FIGS. 4A, 5A, 6A and 7A all
illustrate the stimulation system in various degrees of activation. FIGS.
4B, 5B, 6B and 7B illustrate a correspondingly influenced dermatome.

[0095] FIGS. 4A, 5A, 6A and 7A illustrate a stimulation system 100 having
3 electrodes 115 implanted into dorsal root ganglia 40 on two adjacent
spinal levels. For simplicity, each spinal level illustrates a dorsal
root ganglion 40, a ventral root 41 and a peripheral nerve 44. The
exception is spinal level 3 that illustrates an additional dorsal root
ganglion 38, a ventral root 39 and a peripheral nerve 42. The three
electrodes 115 are designated channels 1, 2 and 3 by the controller 106.
Each electrode is activated to provide modulation energy or signals under
the control of the controller 106. Exemplary electrodes for implantation
into a nerve root ganglion are further described with regard to FIGS.
12A-13B. Level 3 is an example of bilateral electrode placement and level
2 is an example of unilateral electrode placement. As such, the
illustrated embodiment is a multi-level, unilateral and bi-lateral
stimulation system. Stimulation energy is provided by a pulse generator
(not illustrated but described in greater detail below in FIGS. 26-29)
under control of a suitable neurostimulation controller 106. Those of
ordinary skill will recognize that any of a wide variety of known
neurostimulation controllers may be used. Not illustrated in this view
but present in the system are suitable connections between the various
electrodes 115, electrode leads 110 and the controller 106. In the
illustrations that follow, a line connecting the electrode lead 110 to
the controller 106 indicates "stimulation on" communication from the
controller 106 to one electrode 115 (see FIG. 4A) or more than one
electrode 115 (see FIG. 5A).

[0096] A signal of "stimulation on" indicates any of a wide variety of
stimulation patterns and degrees of stimulation. The "stimulation on"
signal may be an oscillating electrical signal may be applied
continuously or intermittently. Furthermore, if an electrode is implanted
directly into or adjacent to more than one ganglion, the oscillating
electrical signal may be applied to one electrode and not the other and
vice versa. One can adjust the stimulating poles, the pulse width, the
amplitude, as well as the frequency of stimulation and other controllable
electrical and signally factors to achieve a desired modulation or
stimulation outcome.

[0097] The application of the oscillating electrical signal stimulates the
area of the nerve chain where the electrode 115 is placed. This
stimulation may either increase or decrease nerve activity. The frequency
of this oscillating electrical signal is then adjusted until the symptoms
manifest by physiological disorder being treated has been demonstrably
alleviated. This may step may be performed using patient feedback,
sensors or other physiological parameter or indication. Once identified,
this frequency is then considered the ideal frequency. Once the ideal
frequency has been determined, the oscillating electrical signal is
maintained at this ideal frequency by storing that frequency in the
controller.

[0098] In one specific example, the oscillating electrical signal is
operated at a voltage between about 0.5 V to about 20 V or more. More
preferably, the oscillating electrical signal is operated at a voltage
between about 1 V to about 30 V or even 40V. For micro stimulation, it is
preferable to stimulate within the range of 1V to about 20V, the range
being dependent on factors such as the surface area of the electrode.
Preferably, the electric signal source is operated at a frequency range
between about 10 Hz to about 1000 Hz. More preferably, the electric
signal source is operated at a frequency range between about 30 Hz to
about 500 Hz. Preferably, the pulse width of the oscillating electrical
signal is between about 25 microseconds to about 500 microseconds. More
preferably, the pulse width of the oscillating electrical signal is
between about 50 microseconds to about 300 microseconds.

[0099] The application of the oscillating electrical signal may be
provided in a number of different ways including, but not limited to: (1)
a monopolar stimulation electrode and a large area non-stimulating
electrode return electrode; (2) several monopolar stimulating electrodes
and a single large area non-stimulating return electrode; (3) a pair of
closely spaced bi-polar electrodes; and (4) several pairs of closely
spaced bi-polar electrodes. Other configurations are possible. For
example, the stimulation electrode(s) of the present invention may be
used in conjunction with another non-stimulating electrode--the return
electrode--or a portion of the stimulation system may be adapted and/or
configured to provide the functionality of a return electrode. Portions
of the stimulation system that may be adapted and/or configured to
provide the functionality of the return electrode include, without
limitation, the battery casing or the pulse generator casing.

[0100] In the illustrated configuration, a stimulation pattern provided to
one of the electrodes positioned in level 3 (i.e., channel #1 "ON")
produces pain blocking/relief in the indicated region of the body (i.e.,
shaded area R1) in FIG. 4B.

[0101] It will be appreciated that embodiments of the present invention
can stimulate specific dermatome distributions to probe which electrode
or group of electrodes or combination of electrodes (including drug
coated or delivery electrodes) is best positioned or correlates most
closely to one or more specific areas of pain. As such, a stimulation
system according to an embodiment of the present invention may be "fine
tuned" to a specific area of coverage or type of pain. The results
obtained from such testing can be used to one or more stimulation or
treatment regimes (i.e., series of stimulations in the presence of or in
combination with a therapeutic agent from a coated electrode) for a
particular patent for a particular type of pain. These pain treatment
regimes may be programmed into a suitable electronic controller or
computer controller system (described below) to store the treatment
program, control and monitor the system components execution of the
stimulation regime as the desired therapeutic regime is executed.

[0102] FIG. 5A provides another example of distribution of pain relief
using a multi-channel stimulation system and method. In the illustrated
configuration and stimulation pattern, a stimulation pattern is provided
to one electrode each in levels 2 and 3 via channels #1 and #2. This
stimulation electrode pattern provides pain blocking/relief in the
indicated region of the body (i.e., areas R1, R2) of FIG. 5B.

[0103] FIG. 6A provides another example of distribution of pain relief
using a multi-channel stimulation system and method. In the illustrated
configuration and stimulation pattern, a stimulation pattern provided to
both electrodes in level 3 via channels #1 and #3 provides pain
blocking/relief in the indicated region of the body (i.e., area R3) of
FIG. 6B.

[0104] FIG. 7A provides another example of distribution of pain relief
using a multi-channel stimulation system and method. In the illustrated
configuration and stimulation pattern, a stimulation pattern is provided
to all electrodes in the system via channels #1, #2 and #3. This
stimulation electrode pattern provides pain blocking/relief in the
indicated region R4 of the body (i.e., FIG. 7B). It is to be appreciated
that the electrode placement and blocking region patterns illustrated by
FIGS. 4A-7B may be modified using information such as in FIGS. 3B and 3C
for targeted placement to specific portions of the body depending upon
individual needs.

[0105] Micro-electrode and stimulation system embodiments of the present
invention may be implanted into a single nerve root ganglion utilizing
the implantation methods of the present invention. The implantation
methods described herein provide numerous advantages, including but not
limited to: low risk percutaneous access route similar to other
procedures, direct delivery of localized quantities of pharmacological
agents at the nerve root when using embodiment having electrodes coated
with pharmacological agents, and electrode placement that enables
preferential, selective nerve fiber stimulation.

[0106] FIG. 8A illustrates a cross section view of a spinal level.
Peripheral nerves 44, 42 feed into dorsal root ganglia 40, 38 and ventral
nerves 41, 39 respectively. A vertebral body 70 and two sympathetic nerve
ganglia 62, 63 are also illustrated. In this embodiment, the method
includes advancing a suitable catheter 107 medially towards the vertebral
body 70, then along the peripheral nerve 42 towards the dorsal root
ganglion 38. The catheter 107 is advanced using external imaging
modalities for guidance such as fluoroscopy or other suitable medical
imaging technique. The vertebral foramen offers a good landmark visible
under fluoroscopy and useful in locating the DRG 38.

[0107] The electrode 115 is implanted in proximity to the dorsal root
ganglion by forming an opening in the dorsal root ganglion epinurium and
passing the electrode through the opening (FIG. 8A, 8B). The opening may
be formed using conventional methods such as a cutting edge on or
provided to the tip of the catheter 107, with an instrument advanced
through a working channel within the catheter 107 or through the use of
other suitable endoscopic or minimally invasive surgical procedure.
Alternatively, the electrode body or distal end may be provided with a
tissue cutting or piercing element to aid in piercing tissue (see, e.g.,
tip 908 in FIG. 20A). As the catheter 107 is withdrawn, the
microelectrode leads 110 are deployed and attached, anchored or otherwise
secured to the tissue, anatomy or bones adjacent the DRG 38 to reduce the
likelihood that electrode 115 will be pulled from the DRG 38. In
alternative embodiments described below, the microelectrode leads 110 may
be fixed prior to electrode implantation into a nerve root ganglion.

[0108] Note that the electrode 115 is sized and shaped to fit within the
DRG 38. A typical DRG is generally spherical with a diameter of 3-5 mm.
Of course, a range of DRG sizes occur in humans and may vary in size
depending on the age and sex of the individual and other factors.
Electrode embodiments may be provided in a range of sizes to accommodate
the specific anatomical characteristics of a patient. A number of factors
are considered when selecting an appropriate DRG electrode embodiment for
use in an individual.

[0109] Electrode placement within the DRG may be confirmed using
neurodiagnostic testing techniques such as somatosensory evoked potential
(SSEP) and electromyography (EMG) adapted for the methods and systems
described herein. One illustrative example includes the placement of
sensing electrodes in the sensory nervous system above and below the DRG
level having the implanted electrode(s). Implant the electrode into the
targeted DRG. Apply a test stimulation to the DRG and measure voltage
potential at the sensory electrodes above and below the targeted DRG to
confirm that the electrode is implanted in the targeted DRG. A test
stimulation may range from 0.4 v to 0.8 v at 50 Hz or may be some other
suitable stimulation level based on the evoked potential measurement
technique used. In this way, conventional fluoroscopy techniques and
instruments may be used to advance towards and implant the electrode into
the DRG and confirm that the electrode is correctly implanted and
stimulating the targeted DRG.

[0110] A number of different approaches are available for maneuvering an
electrode into position on, in or about a DRG. Several exemplary
approaches are provided in FIGS. 8-10 in a section view of the cauda
equina portion of the spinal cord. In these examples, electrodes 115 are
placed on or in a ganglion on a representative sacral spinal level.
Sympathetic nervous system ganglia 62, 63 are also indicated. DRG 40 and
ventral root 41 are associated with peripheral nerve 44. DRG 38 and
ventral root 39 are associated with peripheral nerve 42.

[0111] FIGS. 8A and 8B illustrate a lateral approach to a DRG 38 using a
suitable catheter 107. The catheter advances adjacent to the peripheral
nerve 42 medially towards the DRG 38. The DRG dura is pierced laterally
and the electrode 115 is advanced into the DRG interior. Thereafter, the
electrode 115 is implanted into the DRG interior. Next, as is illustrated
in FIG. 8B, the catheter 107 is withdrawn from the DRG 38 and deploys the
electrode leads 110. The electrode leads 110 may be anchored to the
vertebral body 70 using suitable fixation techniques. The leads 110 are
then connected to a pulse generator/controller (not shown).

[0112] FIG. 9A is anatomically similar to FIGS. 8A and 8B. FIG. 9A
illustrates an alternative DRG implantation approach that crosses the
medial line inferior to the DRG of interest. The catheter 107 is advanced
in a superior pathway towards the foramen and using the foramen under
fluoroscopic guidance into the DRG. As illustrated in FIGS. 9A and 9B,
there is provided a method of stimulating a dorsal root ganglion by
implanting an electrode within the dorsal root ganglion. In some
embodiments, the implanting procedure includes passing a portion of the
electrode through the spinal epidural space. Electrodes in systems of the
present invention onto or in the nerve root epinurium 72 (FIGS. 10A and
10B) or within the nerve root (i.e., FIGS. 9A,B). Moreover, in some
embodiments, there is also the step of forming an opening in the dorsal
root ganglion epinurium 72 and then passing the electrode through the
opening (see, i.e., FIG. 9B).

[0113]FIG. 11 illustrates a section view through a portion of the spinal
cord 13 with another alternative electrode implantation technique. In
contrast to the earlier described methods that externally approach the
DRG and involve piercing or entering the DRG epinurium 72, FIG. 11
illustrates an internal approach to the DRG interlascular from within the
nerve sheath of a peripheral nerve 44. FIG. 11 illustrates a section view
of the nerve sheath partially removed to reveal the underlying nerve
bundle 46. In this illustrative example, an opening is made in the
peripheral nerve 44 sheath at a point 45 lateral to the DRG 40. The
microelectrode 115 enters the nerve 44 sheath through opening 45 using
suitable endoscopic or minimally invasive surgical techniques. Next, the
electrode 115 is advanced towards and into the DRG 40.

[0114] As each of these illustrative embodiments make clear, the placement
of the electrode relative to the DRG enables activating the electrode to
selectively stimulate sensory nerves. Additionally, the placement of the
electrode according to the methods of the invention enable activating the
electrode to stimulate sensory nerves within the DRG or without
stimulating motor nerves in the nearby ventral root. The control system
described herein also provides stimulation levels that activate the
electrode to stimulate at a level that preferably stimulates myelinated
fibers over unmyelinated fibers.

[0115] In addition, as will be described in greater detail below, FIG. 11
illustrates an electrode embodiment where the electrode tip and shaft may
be coated with pharmacological agents to assist in the stimulation
therapy or provide other therapeutic benefit. As illustrated, the
electrode includes a tip coating 130 and a shaft coating 132. The
pharmacological agent in each coating 130, 132 could be the same or
different. One advantage of implanting through the nerve sheath is that
the coated shaft 132 may include a pharmacological agent active or
beneficial to neural activity in the ventral nerve root 41 since this
coated shaft is advantageously positioned proximal to the ventral root
41. The shaft coating 132 may also be selected to reduce inflammation or
irritation caused by the presence of the shaft within the nerve sheath.

[0116] FIGS. 12A and 12B illustrate an embodiment of an exemplary anchor
body 171 with a fixation hook 172 used to secure the leads 110 once the
electrode 115 is implanted into the DRG 40. FIG. 12A is a section view of
a portion of the spinal cord 13 showing the dorsal root 42, ventral root
41, DRG 40 and peripheral nerve 44. In this illustrative embodiment, a
catheter 70 is used to maneuver the electrode 115, leads 110 and anchor
171 about the DRG 40 implantation site. Once a suitable site is
identified, the hook 172 is inserted into the fascia layer of the DRG.
The hook 172 may have various shapes and contours to adapt it to engaging
with and securing to the outer DRG layer or within the outer DRG layer.
FIG. 12B illustrates an exemplary anchor body 171 and hook 172 mounted
onto the distal end of a catheter 70. The anchor body 171 and hook 172
may be maneuvered into position using the catheter 70 alone or in
combination with other suitable surgical, endoscopic or minimally
invasive tools. Similarly, the electrode 115, leads 110 may be moved into
position for implantation on, in or about targeted neural tissue. In
other alternative electrode embodiments, the electrode 115 is implanted
on, in or about a DRG is provided with a flexible tip that helps to
prevent or mitigate chronic friction and ulceration.

[0117] Alternatively, the electrode leads 110 or other supporting or
anchoring structures may be attached to the adjacent bony structure, soft
tissue or other neighboring anatomical structures. In addition, there may
also be provided a fixation, anchoring or bonding structure positioned
proximal to the electrode anchor 172 that absorbs some or all proximal
movement of the leads 110 so that the electrode is less likely to be
pulled from or dislodged from the implantation site. The goal of the
anchoring and other strain absorbing features is to ensure the electrode
remains in place within or is less likely to migrate from the implanted
position because of electrode lead 110 movement (i.e., lead 110 movement
pulls the electrode 115 from the implantation site or disrupts the
position of the electrode 115 within the implantation site). It is to be
appreciated that numerous techniques are available to aid in electrode
placement including percutaneous placement of single/multiple hooks or
anchors, vertebral anchor or posts, micro-sutures, cements, bonds and
other joining or anchoring techniques known to those of ordinary skill in
the art. It is also to be appreciated that other components of the
stimulation system embodiments described herein may also be adapted for
attachment to surrounding tissue in proximity to the stimulation site or
near the electrode implantation site. Other components include, for
example, the stimulation controller, master controller, slave controller,
pulse generator, pharmacological agent reservoir, pharmacological agent
pump and the battery.

[0118]FIG. 12c illustrates an exemplary anchoring of electrode leads 110
to bone surrounding the electrode implantation site. FIG. 12c illustrates
a section view through a portion of the spinal cord 13 showing the
ventral root 41, the dorsal root 42 and dorsal root ganglion 40. FIG. 12c
also illustrates the surrounding bone of the spine such as vertebral body
1110, the spinous process 1115, the pedicle 1120, the lamina 1125, the
vertebral arch 1130, transverse process 1135, and facet 1140. Electrode
115 is implanted into the DRG 40 and the electrode leads are held in
place using a suitable anchor 111. In this embodiment, the anchor 111 is
secured to the vertebral body 1110. The anchor 111 represents any
suitable manner of securing the bony portions of the spine such as tacks,
staples, nails, cement, or other fixation methods known to those in the
surgical or orthopedics arts. A strain relief 122 is present between
anchor 111 and the DRG 40 (see FIGS. 13A and 14A). The strain relief 122
is used to absorb motion that may move the electrode 115 within the DRG
40 or remove the electrode from the DRG 40. In this illustrative
embodiment, the strain relief 122 is a coiled portion of the electrode
lead 110. One or more strain reliefs 122 may be provided between the
anchor 111 and the DRG 40 or between the anchor 111 and the battery or
controller of the stimulation system (not shown).

[0119] FIGS. 13A-14B illustrate mono-polar and bi-polar stimulation
component embodiments of the present invention. FIG. 13A illustrates a
mono-polar stimulation component that has a proximal connector 126A
adapted to be connected to a pulse generator. A distal electrode 115 is
configured to be implanted within the body at a stimulation site. The
distal electrode may be a mono-polar electrode 115A (FIG. 13B) or a
bi-polar electrode 115B (FIG. 14B). The electrodes are sized for
implantation into a nerve root ganglion and will vary according to the
nerve root selected. In additional alternative embodiments, the electrode
leads and electrode are adapted and sized to advance within a nerve
sheath to a nerve root ganglion. The electrodes or their casing may be
made of inert material (silicon, metal or plastic) to reduce the risk
(chance) of triggering an immune response. Electrodes should be studied
for suitability to MRI and other scanning techniques, including
fabrication using radio-opaque materials as described herein.

[0120] Returning to FIG. 13A, an electrical lead 110 is connected to the
proximal connector 126A and the distal electrode 115. A strain relief
mechanism 122 is connected in proximity to the stimulation site. The
illustrated strain relief mechanism is formed by coiling the electrical
lead 110. Other well known strain relief techniques and devices may be
used. A fixation element 124 adapted to reduce the amount of movement of
the electrical lead proximal to a fixation point is positioned in, on, or
through an anatomical structure proximal to the stimulation site.
Multiple elements are provided to mitigate or minimize strain and force
transmission to the micro-leads 110 or the microelectrodes 115 because
the microelectrodes and microelectrode leads used herein are very small
and include fine, flexible wires on the order of 1 mm or less and in many
cases less than 0.5 mm. Representative electrode and lead dimensions will
be described in greater detail below (FIG. 15A, 15B). As such, in some
embodiments, strain and movement may be absorbed or mitigated by the
fixation element 124, the strain relief 122 and the electrode anchor 117
(if included). The fixation element 124 may be, for example, a loop, or a
molded eyelet. The fixation element may be sutured, tacked, screwed,
stapled, bonded using adhesives or joined using other techniques known to
those of ordinary skill to secure the fixation element within the body
for the purposes described herein.

[0121] In one specific implantation embodiment, the method of implanting
the electrode is modified based on consideration of the small size and
delicate nature of the microelectrode and microelectrode leads. As such,
high force actions are taken first followed by light force actions. In
this way, the fine microelectrode and microelectrode lead materials are
not present during high force operations. Consider an example where an
electrode of the present invention will be implanted into a DRG. In an
exemplary embodiment, the fixation element 124 is a loop sized to allow
passage of the electrode 115. Perform the high force operation of
anchoring or otherwise fixing (i.e., adhesion) the fixation element into
a vertebral foramen adjacent the selected DRG stimulation site. In
general, the fixation site should be as close as practical to the
stimulation site. In one specific embodiment, the fixation site is within
3 cm to 5 cm of the stimulation site. Optionally, a guide wire attached
to the loop remains in place and is used to guide the electrode and leads
to the loop and hence to the implant site. The electrode and leads are
passed through the loop (with or without use of a guide wire). The
electrode is then implanted on or in the DRG. Optionally, an anti-strain
device 122 may also be positioned between the electrode in the
implantation site and the fixation element 124. In one illustrative
embodiment, a section of microelectrode lead containing a plurality of
loops is used as an anti-strain device 122. Finally, the microelectrode
lead is secured to the loop using a suitable locking device. It is to be
appreciated that the above method is only illustrative of one method and
that the steps described above may be performed in a different order or
modified depending upon the specific implantation procedure utilized.

[0122] In some embodiments, there may also be provided an anchoring
mechanism proximal to the distal electrode 115. Examples of anchoring
mechanisms include, for example, anchors 117 illustrated in FIGS. 13B and
14B. In still further embodiments, the anchoring mechanism is adapted to
anchor the distal electrode 115 within the stimulation site. For example,
the anchor mechanism may remain stowed flat against the electrode body
118 during implantation and then deploy from within a nerve root ganglion
to anchor against the interior nerve root wall to support the electrode
and prevent electrode migration or pull-out. In some embodiments the
anchoring mechanism and the distal electrode are integrally formed and in
other embodiments they are separate components. In some embodiments, the
anchoring mechanism is formed from a polymer or a silicone.

[0123] Selective nerve stimulation affords the use of smaller electrodes.
Smaller electrodes create less impingement and are less susceptible to
unwanted migration. However, as electrode surface area decreases the
impedance of the electrode increases (FIG. 15A). As such, some electrode
embodiments will have an impedance much greater than the impedance of
conventional stimulation electrodes. In one embodiment, the impedance of
a microelectrode of the present invention is more than 2500Ω. This
difference in impedance also impacts the performance requirements of
stimulation systems, pulse generators and the like used to drive the
microelectrodes described herein.

[0124] Distal electrodes may come in a wide variety of configurations,
shapes and sizes adapted for implantation into and direct stimulation of
nerve root ganglion. For example, the distal electrode 115 may be a ring
of conductive material attached the leads 110. Alternatively, the distal
electrode 115 may be formed from an un-insulated loop of electrical lead.
The loop electrode is appealing and has improved wear properties because,
unlike the ring that must be joined to the leads 110, the loop is formed
from the lead and no joining is needed. In still other embodiments, the
electrode may be an un-insulated portion of the lead.

[0125] Regardless of configuration, electrodes of the present invention
are sized and adapted for implantation into, on or about a ganglion such
as, for example, a dorsal root ganglion or a ganglion of the sympathetic
nervous system. It is to be appreciated that the size of the electrode
varies depending upon the implantation technique and the size of the
target ganglion. An electrode implanted through the DRG dura (i.e., FIG.
9A) may be less than 5 mm since the diameter of a DRG may be only 3-5 mm.
On the other hand an electrode adapted for implantation along the
peripheral nerve sheath (i.e., FIG. 11) may be longer than the electrode
that passes through the dura but may face other design constraints since
it must advance distally within the nerve sheath to reach the DRG. It is
to be appreciated that dimensions of electrode embodiments of the present
invention will be modified based on, for example, the anatomical
dimensions of the implantation site as well as the dimensions of the
implantation site based on implantation method.

[0126]FIG. 15B provides some exemplary electrode surface areas for
electrode embodiments formed from wire diameters between 0.25 mm to 1 mm,
having widths of 0.25 mm or 0.5 mm. As such, embodiments of the present
invention provide distal electrode surface area that is less than 0.5
mm2. In other embodiments, the distal electrode surface area is less
than 1 mm2. In still other embodiments, the distal electrode surface
area is less than 3 mm2.

[0127] The sizes of the electrodes of the present invention stand in
contrast to the conventional paddle 5 having dimensions of about 8 mm
wide and from 24 to 60 mm long (FIG. 1). One result is that conventional
stimulation electrodes have larger electrode surface areas than electrode
embodiments of the present invention. It is believed that conventional
electrodes have an impedance on the order of 500 to 1800Ω operated
using a stimulation signal generated by a 10-12 volt pulse generator. In
contrast, stimulation electrode embodiments of the present invention have
an impedance on the order of 2 kΩ or about 2500Ω, from 2
kΩ to 10 kΩ or higher or even in the range of 10 kΩ to
20 kΩ. As will be described in greater detail below, some pulse
generator embodiments of the present invention operate with voltages
produced by DC-DC conversion into ranges beyond conventional stimulation
systems.

[0128] The electrodes may be formed from materials that are flexible and
have good fatigue properties for long term use without material failure.
The electrode material should be formed from a biocompatible material or
coated or otherwise treated to improve biocompatibility. Additionally,
electrode materials should be opaque to imaging systems, such as
fluoroscopy, used to aid electrode placement during implantation
procedures. Examples of suitable materials include but are not limited to
Pt, Au, NiTi, PtIr and alloys and combinations thereof. Electrodes may
also be coated with a steroid eluding coating to reduce inflammation at
the implantation or stimulation site.

[0129] With the small surface areas, the total energy required for
stimulation of the DRG is drastically reduced because we can achieve high
current densities with low currents. One advantage of using
microelectrodes is that only a small volume of tissues in the immediate
vicinity of the electrodes is stimulated. Another advantage of using
microelectrodes is the correspondingly smaller pulse generator and
because of decreased battery size.

[0130] In addition to the implantable electrodes described above,
alternative electrode embodiments may also be used to selectively
stimulate a nerve root ganglion. FIG. 16 illustrates an embodiment where
conductive rings 205, 207 are positioned on either end of a dorsal root
ganglion 40. When activated, the rings 205, 207 capacitively couple
stimulation energy into the DRG 40. FIG. 17 illustrates an alternative
capacitive stimulation configuration where the capacitive plates 210, 212
are attached to the DRG dura. Embodiments of the present invention are
not limited to only one pair of capacitive plates but more than one pair
may be used. FIG. 18 illustrates two pairs of capacitive plates attached
to the dura of a DRG 40. One pair includes plates 210, 212 and the other
pair includes plate 214 and another plate (not shown). As an alternative
to attaching the plates directly to the dura, the plates may be attached
to an electrode support element 230 adapted to slip around and engage
with the DRG dura. Once the electrode support element 230 is in position
about the DRG, the plates are properly positioned to selectively
stimulate a DRG. The present invention is not limited to only
capacitively coupled stimulation energy. FIG. 20 illustrates another
alternative embodiment where a wire 235 is wrapped around a DRG 40
creating coils 236 that may be used to inductively couple stimulation
energy into a nerve root ganglion. For purposes of discussion, these
embodiments have been described in the context of stimulation a DRG. It
is to be appreciated that the techniques and structures described herein
may also be used to stimulate other nerve root ganglion, other neural
structures or other anatomical features.

[0131] FIGS. 20A and 20B illustrate another electrode embodiment adapted
for implantation through neural tissue. Piercing electrode 900 has a body
902, a distal end 904, and a proximal end 906. A electrode surface or
component 912 receives stimulation signals and energy from a pulse
generator/controller (not shown) via a suitable lead 914. The distal and
904 has a tip 908 adapted to pierce the targeted neural tissue. In
addition, one or more anchors 910 are provided at the distal end to help
secure the electrode body 902 within the targeted neural tissue. A
securing ring 920 (FIG. 20B) is provided to secure the electrode body 902
to or relative to the targeted neural tissue. The anchors 910 may be in a
first or stowed position against the electrode body 902 during insertion
through the neural tissue and then be moveable into a second or deployed
position away from the electrode body 902. In the deployed position
(FIGS. 20A, 20C and 20D) the anchors 910 resist the movement of the
electrode 900 out of the neural tissue. Numerous alternative anchor
configurations are possible. Anchor 910 could be a series of individual
struts arrayed in a circular pattern or struts with material between them
similar to the construction of an umbrella. Anchor 910 could also be a
single anchor.

[0132] The electrode 900 includes a body 902 adapted to pass completely
through targeted neural tissue while positioning the electrode 912 within
a portion of the targeted neural tissue. In this illustrative embodiments
that follow, the electrode body 902 is adapted to fit within a DRG 40
(FIG. 20D) or a ganglion of the sympathetic chain (FIG. 20C). The
electrode 912 may be placed in any location on the electrode body 902 to
obtain the desired stimulation or modulation level. Additionally, the
electrode 912 may be placed so that modulation or stimulation energy
patterns generated by the electrode 912 will remain within or dissipate
only within the targeted neural tissue.

[0133] A securing ring 920 is used to hold the electrode body 902 in
position within and relative to the targeted neural tissue. The securing
ring 920 is ring shaped having an annulus 922. In some embodiments, the
inner surface 942 is used as a friction locking surface to engage and
hold the electrode body 902. In other embodiments, the inner surface 942
contains a surface treatment to secure the electrode body. In still other
embodiments, the inner surface 942 is adapted to mechanically engage with
and secure the electrode body 902. The securing ring 920 may be formed
from a suitable elastic or inelastic material that may be secured to the
electrode body 902 and the outer layer of the targeted neural tissue to
help prevent electrode pull out or dislodgement. The securing ring 920
may be formed from a biocompatible material suited to gluing or
mechanically affixing the ring 920 to the electrode body 902 and the
tissue outer layer. The securing ring 920 may be present during or
positioned after the electrode 900 is implanted into the targeted neural
tissue. In one alternative embodiment, the securing ring 920 is secured
to the DRG outer layer and has a complementary engaging feature
positioned to engage with an engaging feature on the electrode 900. The
electrode body 902 advances through the securing ring annulus 922 and
into the DRG 40 until the complementary engaging features engage and stop
further distal motion of the electrode body 902 into the DRG. The
complementary engaging features may be used alone or in combination with
anchors 910 to assist in electrode 900 placement within neural tissue
such as a DRG or other ganglion.

[0134] FIGS. 20C and 20D illustrate electrode embodiments adapted for
implantation through targeted neural tissue illustrated in a section view
of the spinal cord 13. Additional details of the various portions of the
spinal cord section 14 are described below with regard to FIG. 38. Also
illustrated in these views are exemplary sensory pathways 52/54 and motor
pathways 41P within peripheral nerve 44 and roots 41/42 and entering the
spinal cord. Alternative implantation sites and stimulation alternatives
are described in U.S. Pat. No. 6,871,099, incorporated herein by
reference in its entirety.

[0135] In the illustrative embodiment of FIG. 20C, the electrode 900 is
positioned to remain in a non-central location within the targeted neural
tissue. In this embodiment, the targeted neural tissue is a ganglion 992
within the sympathetic chain 990. Additional details and specific
targeted neural tissue within the sympathetic chain are described below
with regard to FIGS. 32 and 33. The electrode 912 is placed on or in the
electrode body 902 so that when the electrode body 902 passes through the
ganglion 992 and is seated within the securing ring 920 the electrode 912
is in the desired position within the interior of the ganglion 992. Other
electrode 912 placement within the targeted neural tissue is possible,
for example, by varying the length of the electrode body 902, the angle
of penetration into the targeted neural tissue or the position of initial
penetration into the targeted neural tissue.

[0136] In the illustrative embodiment of FIG. 20D, the electrode 900 is
positioned to remain in a generally central location within the targeted
neural tissue. In this embodiment, the targeted neural tissue is a DRG
40. The electrode 912 is placed on or in the electrode body 902 such that
when the electrode body 902 is seated within the securing ring 920, then
the electrode 912 is in the middle of about the middle or center the DRG
40. As before the securing ring 920 and flat anchor 911 secure the
electrode 900 in the desired position within the DRG 40. The flat or flap
anchor 911 provides similar functionality as the anchor 910. The anchor
911 has flat anchors rather than the curved anchors 910.

[0137] In some embodiments, the stimulation electrode tip may be coated
with a pharmacological agent. In the embodiment illustrated in FIG. 21, a
coating 130 covers that portion of the electrode within the DRG 40. In
other embodiments, less or more of the electrode or other implanted
components may be suitably coated to achieve a desired clinical outcome.
FIG. 21 also illustrates a coating 130 on the electrode shaft or portion
of the electrode exterior to the DRG. The coating 132 may be the same or
different than the coating 130. For example, the tip coating 130 may
include a distal coating containing an agent to aid in the effective
stimulation of the DRG. The tip coating 130 may also include a more
proximal coating portion (i.e., near where the electrode pierces the
dura) that contains an agent to prevent fibrous growth about the
electrode. In a further embodiment, the shaft coating 132 would also
contain an agent to prevent fibrous growth about the electrode.
Additionally, the shaft coating 132 may be selected based on providing a
pharmacological agent to interact with the tissue in the ventral root
(i.e., the implantation technique in FIG. 11) or within the peripheral
nerve sheath.

[0138] Examples of desired clinical outcomes provided by pharmacological
agents used as coatings include but are not limited to reduction of scar
tissue development, prevention of tissue growth or formation on the
electrode, anti-inflammation, channel blocking agents and combinations
thereof or other known pharmacological agents useful in treatment of
pain, or neurological pathologies. In other alternative embodiments, the
pharmacological agent may include other compounds that, when placed
within the body, allow the pharmacological agent to be released at a
certain level over time (i.e., a time released pharmacological agent). In
some embodiments, the pharmacological agent is an anti-inflammatory
agent, an opiate, a COX inhibitor, a PGE2 inhibitor, combinations thereof
and/or another suitable agent to prevent pathological pain changes after
surgery. Other suitable pharmacological agents that may be used include
those used to coat cardiac leads, including steroid eluding cardiac leads
or other agents used to coat other implantable devices.

[0139] Embodiments of the present invention include direct stimulation of
a nerve root ganglion or other neurological structure while releasing a
pharmacological agent from an electrode used to provide stimulation. In
one embodiment, the pharmacological agent is released before the
electrode is activated. In other embodiments, the pharmacological agent
is released after or during the electrode is activated. In still other
embodiments, the pharmacological agent is pharmacologically active in the
nerve root ganglion during stimulation of the nerve root ganglion. It is
to be appreciated that embodiments of the present invention may be
altered and modified to accommodate the specific requirements of the
neural component being stimulated. For example, embodiments of the
present invention may be used to directly stimulate a dorsal root
ganglion or a nerve root ganglion of the sympathetic system using the
appropriate pharmacological agents, agent release patterns and amounts as
well as stimulation patterns and levels.

[0140] Turning now to FIG. 22, various stimulation mechanisms are shown.
While these various mechanisms potentate pain, each of them acts on the
primary sensory neuron. The primary modulator of this cell is its cell
body, the DRG 40. One aspect of the present invention is to
advantageously utilize the anatomical placement of the DRG 40 within the
nervous system to complement other treatment modalities. In another
embodiment, stimulation of the DRG 40 as described herein is used in
conjunction with a substance acting on a primary sensory neuron. As
shown, the other mechanisms are nearer to the illustrated tissue injury
than the DRG cell body 40. Put a different way, the DRG 40 is upstream
(i.e., closer to the brain/spinal cord 13) of the other pain mechanisms.
Thus, this is another illustration of how upstream DRG stimulation may be
used to block and/or augment another pain signals.

[0141] Electrophysiological studies suggest that Prostaglandin E2 (PGE2),
produced by COX enzymes, increases the excitability of DRG neurons in
part by reducing the extent of membrane depolarization needed to activate
TTX-R Na+ channels. This causes neurons to have more spontaneous firing
and predisposed them to favor repetitive spiking (translates to more
intense pain sensation). Also illustrated here is how other
pro-inflammatory agents (Bradykinin, Capsaicin on the Vanilloid Receptor
[VR1]) converge to effect the TTX-R NA+ channel. Opiate action is also
upstream from the TTX-R Na+ channel modulation. Embodiments of the
present invention advantageously utilize aspects of the pain pathway and
neurochemistry to modify electrophysiological excitability of the DRG
neurons where electrical stimulation is coupled with pharmacological
agents (electrical stimulation alone or in combination with a
pharmacological agent) to optimize the efficacy of the stimulation
system.

[0142] Synergy of electrical and pharmacological modulation may also be
obtained using a number of other available pharmacological blockers or
other therapeutic agents using a variety of administration routes in
combination with specific, directed stimulation of a nerve root ganglion,
a dorsal root ganglia, the spinal cord or the peripheral nervous system.
Pharmacological blockers include, for example, Na+ channel blockers, Ca++
channel blockers, NMDA receptor blockers and opioid analgesics. As
illustrated in FIGS. 23A and 23B, there is an embodiment of a combined
stimulation and agent delivery electrode. Note the bipolar electrodes
115B on the tip, the coating 130 and the beveled tip shape for piercing
the dura during implantation. The electrode tip is within the DRG
epinurium 72 and well positioned to modify and/or influence c-fiber 55
responsiveness. In the illustration, circles represent Na+ ions,
triangles represent Na+ channel blockers (such as, for example,
dilantin--[phenytoin], tegretol--[carbamazapine] or other known Na+
channel blockers). As the agent is released from coating 130, receptors
on c-fiber 55 are blocked thereby decreasing the response of the c-fiber
below the response threshold (FIG. 23B). Because the activation potential
of the c-fiber has been lowered, the larger diameter A-fiber is
preferentially stimulated or the response of the A-fiber remains above
the threshold in FIG. 23B.

[0143] Embodiments of the present invention also provide numerous
advantageous combinational therapies. For example, a pharmacological
agent may be provided that acts within or influences reactions within the
dorsal root ganglia in such a way that the amount of stimulation provided
by electrode 115B may be reduced and yet still achieve a clinically
significant effect. Alternatively, a pharmacological agent may be
provided that acts within or influences reactions within the dorsal root
ganglia in such a way that the efficacy of a stimulation provided is
increased as compared to the same stimulation provided in the absence of
the pharmacological agent. In one specific embodiment, the
pharmacological agent is a channel blocker that, after introduction, the
c-fiber receptors are effectively blocked such that a higher level of
stimulation may be used that may be used in the presence of the channel
blocking agent. In some embodiments, the agent may be released prior to
stimulation. In other embodiments, the agent may be released during or
after stimulation, or in combinations thereof. For example, there may be
provided a treatment therapy where the agent is introduced alone,
stimulation is provided alone, stimulation is provided in the presence of
the agent, or provided at a time interval after the introduction of the
agent in such a way that the agent has been given sufficient time to
introduce a desired pharmacological effect in advance of the applied
stimulation pattern. Embodiments of the stimulation systems and methods
of the present invention enable fine tuning of C-fiber and Aβ-fiber
thresholds using microelectrodes of the present invention having
pharmacological agent coatings coupled with electrical stimulation.
Representative pharmacological agents include, but are not limited to:
Na.sup.+ channel inhibitors, Phenytoin, Carbamazapine, Lidocaine GDNF,
Opiates, Vicodin, Ultram, and Morphine.

[0144] FIGS. 23C and 23D illustrate alternative embodiments for
combination neurostimulation and pharmacological agent delivery systems.
Additional details of the controller and pulse generated systems suitable
for these operations are described below with reference to FIGS. 26-29.
While described using combined pump and reservoir delivery systems, it is
to be appreciated that the pump for moving the pharmacological agent from
the reservoir to and out of the electrode and the reservoir for storing
the pharmacological agent before delivery may be two separate components
that operate in a coordinated fashion. Pumps and reservoirs may be any of
those suited for controlled delivery of the particular pharmacological
agent being delivered. Suitable pumps include any device adapted for
whole implantation in a subject, and suitable for delivering the
formulations for pain management or other pharmacological agents
described herein. In general, the pump and reservoir is a drug delivery
device that refers to an implantable device that provides for movement of
drug from a reservoir (defined by a housing of the pump or a separate
vessel in communication with the pump) by action of an operatively
connected pump, e.g., osmotic pumps, vapor pressure pumps, electrolytic
pumps, electrochemical pumps, effervescent pumps, piezoelectric pumps, or
electromechanical pump systems. Additional details of suitable pumps are
available in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,298,003 and
6,835,194, each of which is incorporated herein by reference in their
entirety.

[0145] FIG. 23C illustrates a combined system controller and pulse
generator 105B adapted to control the delivery of pharmacological agents
from the agent reservoir and pump 195. The pharmacological agent pumped
from the agent reservoir and pump 195 travels via a dedicated conduit
into a common supply 110F, through a strain relief 122F and into the
agent and stimulation electrode 2310. The common supply 110F may be a
single line containing both electrode control and power signals from the
controller 105B as well as agent delivered from the pump 195 or there
could be two separate lines joined together. Regardless of configuration,
common supply 110F simplifies implantation procedures because a single
line is used to connect the electrode 2310 to the controller 105B and the
pump 195.

[0146] The combination neurostimulation and pharmacological agent delivery
electrode 2310 includes a body 2312 adapted to fit within targeted neural
tissue. In this illustrative embodiment, the electrode body 2310 is
adapted to fit within a DRG 40. An electrode 2318 is positioned on or in
the electrode body 2312 or may be the electrode body 2312. The electrode
2318 is adapted to receive signals and power from the pulse generator
105B via the common supply 110F. The electrode 2318 may be placed in any
location on the electrode body 2312 to obtain the desired stimulation or
modulation level. Additionally, the electrode 2318 may be placed so that
modulation or stimulation energy patterns generated by the electrode will
remain within or dissipate only within the targeted neural tissue. In
this illustrative embodiment, the electrode 2318 is positioned to remain
in a generally central location within the targeted neural tissue. In
this embodiment, the targeted neural tissue is a DRG 40. The electrode
2318 is placed on or in the electrode body 2312 such that when the
electrode 2310 is seated within the securing ring (described below), then
the electrode 2318 is in the middle of about the middle or center the
DRG.

[0147] A securing ring 2315 is used to hold the electrode body 2312 in
position within and relative to the DRG 40. The securing ring 2315 may be
formed from a suitable elastic or inelastic material that may be secured
to the electrode body 2312 and the outer DRG layer to help prevent
electrode pull out or dislodgement. The securing ring 2315 may be formed
from a biocompatible material suited to gluing or mechanically affixing
the ring 2315 to the electrode body 2312 and the DRG outer layer. The
securing ring 2315 may be present during or positioned after the
electrode 2310 is implanted into the DRG. In one alternative embodiment,
the securing ring is secured to the DRG out layer and has a complementary
engaging feature positioned to engage with an engaging feature on the
electrode 2310. The electrode body 2312 advances through the securing
ring 2315 and into the DRG 40 until the complementary engaging features
engage and stop further distal motion of the electrode body 2312 into the
DRG. The complementary engaging features may be used to prevent an
electrode 2310 intended to be positioned within a DRG from piercing
through a DRG.

[0148] There is at least one conduit or lumen (not shown) within the
electrode body 2312 that provides communication from the portion of the
common supply 110F containing the pharmacological agent to the distal
opening 2316. In operation, pharmacological agent(s) within the
pump/reservoir 195 are delivered, under the control of controller 105B,
to the common supply 110F, through the electrode body 2312 and out the
distal opening 2316 into the DRG interior. Note that this embodiment of
the distal opening 2316 contains a beveled edge that may be used to
pierce the DRG during the implantation procedure.

[0150] In contrast to FIG. 23C that uses a combined controller, pulse
generator and battery 105B, the configuration in FIG. 23D provides a
distributed system similar to those described with regard to FIGS. 28 and
29. A pulse generator and controller 105C and a pharmacological agent
reservoir and pump 2395 receive power from battery 2830 using suitable
connections 2307 and 2305, respectively. The pharmacological agent
reservoir and pump 2395 may have its own controller operated
independently of the controller/generator 105C, have its own controller
operated under the control of the controller/generator 105C (i.e., in a
master/slave relationship) or be operated under the control of the
controller/generator 105C. Electrode 912 receives stimulation power from
generator 105c via leads 110. Perfusion ports 928 are connected via one
or more conduits (not shown) within the electrode body 902 and the
conduit 2396 to the pharmacological agent reservoir and pump 2395.

[0151] The embodiment of electrode 900A is similar to the electrode 900 of
FIG. 20A. Electrode 900A also includes perfusion ports 928 within the
electrode body 902 that are in communication with the contents of the
pump and reservoir 2395 via the conduit 2396. The electrode body 902 is
long enough for implantation through targeted neural tissue. While
illustrated implanted generally central to a DRG 40, it is to be
appreciated that the electrode body 902 may be longer or shorter to
accommodate different sizes of targeted neural tissue or different
placement within neural tissue. For example, FIG. 20C illustrates an
embodiment of electrode 900 implanted in a non-central position within a
ganglion of the sympathetic chain. The electrode 900A includes a proximal
end 904 with tip 908 and anchors 910. A securing ring 920 (described
above) is provided to secure the electrode body 902 to or relative to the
DRG 40. The anchors 910 may be in a first or stowed position against the
electrode body 902 during insertion through the DRG and then be moveable
into a second or deployed position away from the electrode body 902. In
the deployed position (FIG. 23D) the anchors 910 resist the movement of
the electrode 900A out of the DRG 40. Numerous alternative anchor
configurations are possible. Anchor 910 could be a series of individual
struts arrayed in a circular pattern or struts with material between them
similar to the construction of an umbrella. Anchor 910 could also be a
single anchor.

[0152] The electrode 912 and perfusion ports 928 may be positioned along
the electrode body 902 in any position suited for the delivery of
neurostimulation and pharmacological agents. In the illustrated
embodiment, the electrode 912 is positioned generally central within the
DRG and the perfusion ports 928 are near the distal end of the electrode
body 902. Other configurations are possible and more or fewer electrodes
and perfusion ports may be used in other embodiments. For example, a
perfusion port 928 could be located near the center of the DRG while an
electrode 912 could be located elsewhere on the electrode body 902 so as
to minimize the stimulation energy transmitted beyond the DRG and into
surrounding tissue. One or more electrodes 912 could be positioned along
the electrode body 902 so that the stimulation energy remained within
(i.e., nearly completely attenuated within) the DRG 40 or other targeted
neural tissue.

[0153] In one specific embodiment, the distal tip 908 has a point suited
for piercing the dura layers to provide access for the electrode body 902
through the DRG. The tip 908 is advanced through the DRG until the
anchors 910 pass through the opening formed by the tip 908 and extend as
shown in FIG. 23D. Once the anchors 910 are through the DRG and extended,
the electrode body 902 may be withdrawn slightly to engage the anchors
910 against the DRG dura. Thereafter, the securing ring 920 is advanced
into position around the electrode body 902 and against the outer layer
of DRG 40. When implanted into the DRG 40, electrode 900A is held in
place using the anchors 910 and the securing ring 920. In other
embodiments, the securing ring 920 may be used without the anchors 910.
In another embodiment, the anchors 910 are used without the securing ring
920 or the securing ring 920 is replaced by another set of anchors that
are adapted to secure the proximal end of the electrode body 902 to or in
proximity to the DRG.

[0154]FIG. 24 is a table that includes several exemplary infusion
pharmacological agents. The pharmacological agents are listed along the
left side. Moving to the right, closed circles and open circles are used
to indicate the level of support for using a particular pharmacological
agent with a particular type of pain or other condition. Closed circles
indicate evidence from controlled trials or several open-label trials and
general acceptance or utility. Open circles indicate a less extensive
base of evidence. For example in the treatment of restless leg syndrome
(RLS), benzodiazepines have evidence of general acceptance or utility
while gabapentin has a less extensive base of evidence. These and other
pharmacological agents may be provided into the body to have a
cooperative pharmacological result on the neural tissue(s) either alone
or in combination with stimulation provided by embodiments of the present
invention. In some embodiments, the pharmacological agent is provided at
the stimulation site and in other embodiments the pharmacological agent
is provided using a stimulation electrode embodiment adapted to deliver
one or more pharmacological agents.

[0155] Consider the following specific example. Nociceptors express a
specific subclass of voltage-gated sodium channel. These TTX-R Na+
channels are believed to contribute significantly to action potential
firing rate and duration in small-diameter sensory neurons (i.e.,
c-fibers). Embodiments of the present invention may provide the
appropriate channel blocker to synergistically improve neurostimulation
capabilities. For example, a combination stimulation and release of a
pharmacological agent may be used to provide Na channel blockers directly
within the dorsal root ganglia interfascicular space, adjacent to c-fiber
or within a pharmacologically active position such that the agent
interacts with the channel.

[0156] Embodiments of the present invention also enable the advantageous
use of ion channels in the nervous system as targets for pharmacological
agents combined with selective direct stimulation. Na.sup.+ channels and
gabapentin sensitive Ca2+ channels are upregulated after
nerve-injury. Channel blockers can suppress abnormal C-fiber neural
excitability. Na.sup.+ and Ca.sup.+ channel targets distributed along the
pain pathway are illustrated in FIG. 25. Embodiments of the present
invention advantageously utilize the specific anatomy and features of the
dorsal root ganglia (DRG) to improve the efficacy of pharmacological
agents. In one specific example, note that the DRG contains both
TTX-sensitive NA+ channels (Nav1.3), TTX-resistant Na+ channels
(1.8,1.9), and gabapentin sensitive Ca2+ channels. FIG. 25 shows a number
of dorsal root ganglia, peripheral nervous system and spinal cord
afferent pain pathways. Note the alterations in voltage-dependent Na+ and
Ca2+ channel subunits after chronic nerve injury associated with
neuropathic pain. In addition, there is an increase in the expression of
Nav1.3 channels and Na+ channel 3 (Nav 3) and Ca2+ channel 2-1 (Cav 2-1)
subunits in dorsal root ganglion neuron cell bodies, and in the
expression of Nav1.3 in second-order nociceptive neurons in the spinal
cord dorsal horn 37. The tetrodotoxin-resistant Na+ channel subunits
Nav1.8 and Nav1.9 are also redistributed from dorsal root ganglion neuron
cell bodies to peripheral axons and pain receptors at the site of injury.
These changes are thought to result in spontaneous ectopic discharges and
lower the threshold for mechanical activation that leads to
paraesthesias, hyperalgesia and allodynia.

[0157] In one aspect of the present invention, these channels are the
target of a stimulation provided by embodiments of the systems and
stimulation methods of the present invention. The stimulation may include
electrical stimulation alone, a pharmacological agent delivered directly
or via the DRG, a pharmacological agent delivered directly or via the DRG
in combination with electrical stimulation, or electrical stimulation of
the DRG in combination with the delivery of a pharmacological agent
elsewhere in the pain pathway. In one particular embodiment, delivery of
a pharmacological agent elsewhere in the pain pathway is upstream of the
dorsal root ganglion or the nerve root ganglion being stimulated. In
another embodiment, delivery of a pharmacological agent elsewhere in the
pain pathway is downstream of the dorsal root ganglion. In another
specific embodiment, stimulation is provided to a nerve ganglion in the
sympathetic nervous system and a dorsal root ganglion up stream of or
otherwise positioned to influence or block signals originating from the
nerve ganglion.

[0158] Alternative embodiments of the methods and systems of the present
invention may be used to repair or assist in the repair of neurological
tissue in the spinal cord.

[0159] In another aspect of the present invention, there is provided
methods and systems for the selective neurostimulation of the dorsal root
ganglia for the regeneration of neurological tissue. For example,
electrical stimulation may be provided selectively to the DRG, a portion
of the DRG or in proximity to the DRG with or without a pharmacological
agent to produce conditions within the DRG to assist in, encourage or
otherwise promote the regeneration of neurological tissue.

[0160] In a specific embodiment where pharmacological agents may be
provided by embodiments of the present invention, there is provided a
method and/or system to induce intraganglionic cAMP elevation for the
regeneration of sensory axons utilizing the mechanisms suggested by
Neumann S, Bradke F, Tessier-Lavigne M, Basbaum A I. In the article
entitled, "Regeneration of Sensory Axons Within the Injured Spinal Cord
Induced by Intraganglionic cAMP Elevation. (see Neuron. 2002 Jun. 13;
34(6):885-93, incorporated herein by reference in its entirety.) The work
of Neuman et al. demonstrated the regeneration of the central branches of
sensory neurons in vivo after intraganglionic injection of db-cAMP.
Horizontal sections through a lesion site taken from db-cAMP-injected
animals shows regenerating fibers. A neurostimulation electrode adapted
for delivery of a pharmacological agent may be used for intraganglionic
delivery of db-cAMP. Intraganglionic delivery of db-cAMP may be
accomplished using any of the techniques described herein for the
delivery of a pharmacological agent including, for example, a coating on
all or part of an electrode body or the use of suitably positioned
perfusion ports.

[0161]FIG. 26 illustrates an embodiment of a pulse generator 105
according to one aspect of the present invention. Similar to conventional
stimulation pulse generators, communication electronics 102 have a
receiver for receiving instructions and a transmitter for transmitting
information. In one embodiment, the receiver and the transmitter are
implantable in the body and adapted receive and transmit information
percutaneously. The control electronics 106 includes a microcontroller
103 having conventional features such as program memory 103.1, parameter
and algorithm memory 103.2 and data memory 103.3. A battery 130 is also
provided and may be located with and part of the pulse generator (i.e.,
FIG. 27) or implanted at a location separate from the pulse generator
(i.e., FIG. 28). Switches 109 are provided to couple stimulation energy
from the DC-DC converter 113 to the stimulation sites (i.e., electrodes
located at STIM1-STIM4) under the control of the microcontroller 103.

[0162] Programmable parameters are modified in accordance with
transcutaneous RF telemetry information received by communication
electronics 102. The telemetry information is decoded and used by the
control electronics to modify the pulse generator 105 output as needed.
The output of the pulse generator or a stimulation program may be
modified dynamically. Pain often correlates to certain activities such as
walking, bending or sitting. An activity level sensor may be used to
detect the amount or degree of activity. The level of activity could be
an input to dynamically modify the stimulation program to determine the
appropriate level of stimulation. Alternatively or additionally,
different pre-programmed stimulation algorithms may be designed for an
individual patient based on that specific patient's pattern of activity.
Pre-programmed stimulation algorithms may be stored in an appropriate
medium for use by a stimulation system described herein. Conventional
transcutaneous programming techniques may also be used to update, modify
or remove stimulation algorithms.

[0163] Pain often correlates to certain positions such as standing or
laying down. A position sensor may be used to detect position of the
patient. The position of the patient could be an input to the stimulation
control system to dynamically modify the stimulation program to determine
the appropriate level of stimulation. One example of such a sensor is a
multi-axis accelerometer. A conventional 3 or 4 axis accelerometer could
be implanted into a patient or maintained on the patient to provide
position, activity level, activity duration or other indications of
patient status. The detected indications of patient status could in turn
be used in determining stimulation level and pattern. The position sensor
can be set up or calibrated once positioned or implanted on or in a
person. The calibration aids the sensor in correctly recognizing the
persons orientation and activity levels.

[0164] Optionally, a position sensor 108 is located within the same
physical housing as implantable generator. If desired, the position
sensor may be located elsewhere on the body in an implanted location or
may be worn externally by the person. Position information from the
position and/or activity sensor 108 is provided to the pulse generator
105 using suitable means including direct connections or percutaneous
transmission. Although a number of embodiments are suitable, the
preferred mode employs, by way of example and not to be construed as
limiting of the present invention, one or more accelerometers to
determine patient state including, at least, the ability to sense whether
the person is erect or recumbent. Additionally, the position sensor could
be adapted to provide an indication of activity or level of activity such
as the difference between walking and running. In another embodiment, a
position sensor 108 may be positioned to sense specific motion such as
activity of a particular part of the body to detect specific movement of
a body part or limb that, for example, is undergoing post-surgical
physical therapy. Using this position sensor embodiment, when the person
started activity related to physical therapy, the sensor would detect
such activity and provide the appropriate stimulation. In additional
alternatives, the position and/or activity sensor includes one or more
multi-axis accelerometers.

[0165] As discussed above, microelectrode embodiments of the present
invention have electrode sizes and surface areas that are considerably
smaller that conventional stimulation electrodes so that they may be
implanted according to the methods described herein. As discussed above,
the smaller electrode size leads to increased electrical impedance and a
need for voltages above 15 volts, above 20 volts or even up to as much as
40 volts in order to provide sufficient stimulation current to the
microelectrode. Conventional pulse generators employ capacitive switching
arrays to provide voltages up to 12 v from a 3 v battery for conventional
neurostimulation systems. It is believed that the large electrical losses
introduced by the switches used in conventional capacitive systems would
render them incapable of providing sufficient current to drive the
microelectrodes of the present invention. As such, the pulse generator
105 departs from conventional pulse generators by using a DC-DC converter
to multiply the battery voltage up to the ranges needed to operate the
stimulation systems described herein.

[0166] In one embodiment of the pulse generator of the present invention,
there is at least one switch 109 connected to at least one implantable
electrode having an impedance greater than 2,500 ohms. There is also
provided a DC-DC converter adapted to provide a stimulation signal to the
at least one implantable electrode under the control of the controller
103 that is configured to control the output of the DC-DC converter 113.
Additionally, the pulse generator, the at least one switch, the DC-DC
converter and the controller are implantable in the body. In another
aspect, the controller 103 controls the output of the DC-DC converter 113
to deliver a stimulation signal according to an algorithm for blocking
pain signals. In one aspect, the DC-DC converter is configured to provide
a voltage from 0 volts to 30 volts. In another aspect, the DC-DC
converter is configured to provide a voltage from 0 volts to 40 volts.

[0167]FIG. 27 illustrates one embodiment of an electrode connector
according to the present invention. The electrode connector 120 has a
proximate end 123 adapted to connect with a pulse generator 105A and
distal end 121 adapted to connect with the electrode connector 126. The
electrode connector distal 121 end is adapted to connect to a plurality
of microelectrode leads 110/connectors 126 depending upon how many
microelectrodes 115 are used. Optionally, a portion of the electrode
connector 120 may be configured as a return electrode in some
embodiments.

[0168] In conventional stimulation systems, the stimulation electrode
leads are connected directly to the pulse generator resulting in an
implantation procedure that includes tunneling multiple leads from the
pulse generator to each electrode. This technique has the added
shortcoming of multiple connection points into the pulse generator each
one required to be sealed and a source of potential wear. In contrast,
embodiments of the present invention utilize fine micro leads 110 and
microelectrodes 115 that would likely hinder the success of conventional
tunneling procedures. Rather than the conventional tunneling of multiple
electrodes and their leads, the electrode connector 120 is a flexible
electrical connector used to bridge the distance between the site where
the pulse generator is implanted and the one or more stimulation sites
where the microelectrodes will be implanted. It is to be appreciated that
the electrode connector is sufficiently long to extend from the pulse
generator implanted at a first anatomical site to the microelectrode
implanted at a second anatomical site.

[0169] The pulse generator 105A differs from conventional pulse generators
in that is has a single connection point to the electrode connector
rather multiple connection points to each stimulation electrode.
Advantageously, the fine micro leads and microelectrodes are thus
implanted and span a distance now made much shorter by the electrode
connector 120. The microelectrode leads 110 now only span a distance
between the electrode connector distal end 121 and the microelectrode 115
at the nerve root ganglion implantation site.

[0170]FIG. 27 also illustrates an embodiment of a stimulation component.
The stimulation component includes a proximal connector 126, a distal
electrode 115 configured to be implanted within the body at a stimulation
site and an electrical lead 110 connected to the proximal connector and
the distal electrode. The distal electrode may be, for example, a
mono-polar electrode or a bi-polar electrode. In some embodiments, there
is also provided a strain relief mechanism in proximity to the
stimulation site and/or a fixation element adapted to reduce the amount
of movement of the electrical lead proximal to a fixation point in an
anatomical structure proximal to the stimulation site (See e.g., 12A/B,
13A, 14A). The proximate connector 126 is adapted to connect with the
electrode connector distal end 121.

[0171] In still further embodiments, the stimulation component may also
include an anchoring mechanism proximal to the distal electrode (e.g.,
deformable anchor 117 in FIG. 13B, 14B). In some embodiments, the
anchoring mechanism is adapted to anchor the distal electrode within the
stimulation site and may optionally be integrally formed with the distal
electrode. The anchoring mechanism is formed from a polymer, a silicone
or other flexible, biocompatible material. In some embodiments, the
anchoring mechanism and/or the electrode body is formed from a flexible,
biocompatible material that has been adapted to include a radio opaque
material. Suitable biocompatible materials may biocompatible polymeric
biomaterials featuring radio-opacity or other polymeric biomaterials made
radio-opaque through addition of a `contrast agent`, usually a non-toxic
salt or oxide of a heavy atom.

[0172]FIG. 28 illustrates another stimulation system embodiment of the
present invention. In the illustrative embodiment, a pulse generator 2806
is connected to four individually controlled microelectrodes 115
implanted in four separate nerve root ganglion, here dorsal root
ganglions DRG1 through DRG4. The innovative stimulation system of FIG. 28
differs from conventional stimulation systems in that the battery 2830 is
separate from the pulse generator 2806. An electrical connection (e.g.,
wires 2804) suited to carry the battery power extends from the battery
2830 to the pulse generator 2806. A microelectrode lead 110 is connected
proximally to the pulse generator 2806 using connectors 2812 and distally
to a microelectrode 115. The pulse generator 2806 includes similar
functionality of earlier described pulse generator embodiments such as a
DC-DC converter configured to provide a voltage from 0 volts to 30 volts,
a voltage from 0 volts to 40 volts or other suitable voltage ranges to
drive microelectrodes described herein. The battery 2830, the pulse
generator 2806 separate from the battery, the electrical connections
2804, the microelectrode lead 110 and the microelectrode 115 are adapted
to be implanted in the body.

[0173] Additional embodiments of the local pulse generator 2806 have a
compact size that enables implantation of the pulse generator 2806 in
proximity to the stimulation site. Implanting the local pulse generator
2806 closer to the implantation site of the microelectrodes 115 desirably
allows the use of shorter microelectrode leads 110. Embodiments of the
pulse generator 2806 are sufficiently small to allow implantation in the
back near the spinal levels to be stimulated, the upper back near the
C1-C3 levels for migraine relief (FIG. 30). In one specific embodiment,
the pulse generator 2806 has an overall volume of less than 200 mm3.
In another specific embodiment, at least one dimension of the pulse
generator 2806 is 2 mm or less or at least one dimension of the pulse
generator 2806 is 10 mm or less.

[0174] One embodiment of a multiple pulse generator system is illustrated
in FIG. 29. The multiple pulse generator embodiment is similar to the
system of FIG. 28 with the addition of a second pulse generator 2806B
connected to the first pulse generator 2806A at connection points 2810
using connectors 2814. As with the earlier system, the second pulse
generator 2806B is separate from the battery 2830. Additionally, there
are provided microelectrode leads 110 connected proximally using
connectors 2812 to the second pulse generator 2806B and distally to
microelectrodes 115. The microelectrodes 115 are implanted within nerve
root ganglia, here, dorsal root ganglia at implantation sites DRG5-DRG8.
FIG. 29 illustrates eight implanted electrodes in separate implantation
sites that could include dorsal root ganglion, nerve root ganglion of the
sympathetic nervous system or other stimulation sites within the body.

[0175] It is to be appreciated that in one aspect the pulse generator 2806
and the second pulse generator 2806B are independently programmable. In
another aspect, the pulse generator 2806A and the second pulse generator
2806B are adapted to operate in a master-slave configuration. Numerous
coordinated stimulation patterns are possible for each electrode of a
pulse generator or of all the electrodes in the system. In still further
aspects, the activation of one microelectrode is coordinated with the
activation of a second microelectrode. In one specific aspect, the
microelectrode and the second microelectrode are activated by the same
pulse generator. In another specific aspect, the microelectrode is
activated by the pulse generator 2806A and the second microelectrode by
the second pulse generator 2806B in a coordinated manner to achieve a
therapeutic outcome. For example, the microelectrode is active when the
second microelectrode is active or the microelectrode is inactive when
the second microelectrode is active. In still further embodiments, the
microelectrode is implanted in a dorsal root ganglion and the second
microelectrode is implanted in a nerve root ganglion of the sympathetic
nervous system. It is to be appreciated that the systems of FIGS. 27 and
28 may be configured as discussed above with regard to FIGS. 3-7.

[0176] In additional alternative aspects, specific embodiments of the
present invention may be used to provide direct stimulation alone or in
combination with released therapeutic agents as described herein for the
treatment of headaches, migraine etc. As such, embodiments of the present
invention may be used to provide direct, selective DRG, spinal cord
and/or peripheral nervous system stimulation (using stimulation alone or
in combination with the delivery of a therapeutic agent as described
herein) to all, part or a combination of the C1-C3 levels to provide
relief, reduction or mitigation of pain resulting from headache, migraine
or other such related conditions. There is provided a method of
stimulating neural tissue to treat a condition by stimulating an
electrode implanted to stimulate only a dorsal root ganglion on a spinal
level wherein the stimulation treats the condition. As illustrated in
FIG. 30, the spinal level comprises C1, C2 or C3 and the condition is a
headache, or more specifically, a migraine headache.

[0177] In another alternative aspect, embodiments of the present invention
provide sensory augmentation as a treatment for diabetic neuropathy. In
one embodiment, direct stimulation of the DRG, spinal cord and/or
peripheral nervous system using the techniques described herein are
provided to stimulate or otherwise generate a type of stochastic
resonance that will improve, enhance or provide added neurological
stimulation. Stochastic resonance is the addition of noise to a system to
improve signal clarity. For example, the introduction of direct
neurological stimulation to the appropriate DRG, group of DRG, the spinal
cord and/or peripheral nervous system may provide, for example, improved
vestibular balance or other improvement or mitigation of a condition
induced by diabetic neuropathy. The added neurological stimulation
(either stimulation alone or in combination with therapeutic agent(s))
may be used, for example, to improve the nerve fiber function of nerve
fibers damaged, improperly functioning or otherwise impaired as a result
of diabetic neuropathy. Exemplary stimulation patterns induced utilizing
direct stimulation techniques described herein to help raise the
sub-threshold signal (FIG. 31A) to or above the threshold level (FIG.
31B).

[0178] In other embodiments of the present invention there are provided
methods of treating physiological disorders by implanting at least one
stimulation electrode at a specific location along the sympathetic nerve
chain. Preferably, the present invention provides a method of
therapeutically treating a variety of physiological disorders or
pathological conditions by surgically implanting an electrode adjacent or
in communication to a predetermined site along the sympathetic nerve
chain on the affected side of the body or, if clinically indicated,
bilaterally. FIG. 32 illustrates a schematic of the autonomic nervous
system illustrating sympathetic fibers and parasympathetic fibers,
including several nerve root ganglion.

[0179] Accordingly, embodiments of the present invention may be used in
conjunction with other neurostimulation techniques by combining an
upstream stimulation using specific DRG stimulation of the present
invention with another stimulation acting downstream of the DRG
stimulation. As used herein, downstream and upstream refer to pathways
closer to the brain (i.e., upstream) or further from the brain (i.e.,
downstream). For example, several stimulation techniques are described by
Rezai in US Patent Publication No. 2002-0116030 and U.S. Pat. No.
6,438,423 and by Dobak in U.S. Patent Publication NO. 2003-0181958, all
of which are incorporated herein by reference. In specific aspects,
embodiments of the present invention may be used to provide electrical
and combinational (i.e., with a pharmacological agent) stimulation of the
sympathetic nerve chain as described by Rezai alone (i.e., using the
appropriate DRG stimulation or implanting directly into a nerve root
ganglion.). Alternatively or additionally, embodiments of the present
invention provide specific, direct stimulation of one or more DRG are
used in combination with the stimulation techniques described by Rezai
(i.e., conventional stimulation of the sympathetic chain using one or
more of Rezai's techniques).

[0180]FIG. 33 illustrates how embodiments of the present invention may be
advantageously utilized for neurostimulation of the sympathetic chain
using direct stimulation of the associated DRG. This aspect of the
present invention takes advantage of the anatomical placement of the DRG
relative to the sympathetic chain in conjunction with gate control theory
described herein to direct DRG stimulation for control of the sympathetic
system. Thus, selective neurostimulation techniques of the present
invention may be advantageously employed to, for example, provide and/or
augment therapeutic tools in regards to weight control, hormonal
regulation, vascular perfusion, etc. Additional alternative embodiments
include the use of specific stimulation to provide organ system autonomic
modulation. Through implantation of stimulation electrodes and systems of
the present invention to stimulate the appropriate DRG upstream of the
associated portion(s) of the sympathetic chain, the associated system may
be controlled, modulated or influenced utilizing the electrical and/or
pharmacological agent stimulation techniques described herein.

[0181] In one specific example, by stimulating the DRG 40 associated with
spinal level 13.3, the portion of the sympathetic chain associated with
hormonal regulation may be altered, modified, influenced or controlled.
Similarly, by stimulating the DRG 40 associated with spinal level 13.2
and/or level 13.1, the portion of the sympathetic chain associated with
the gastrointestinal tract, or urinary incontinence (i.e., urinary
bladder, urethra, prostate, etc.) may be altered, modified, influenced or
controlled. Additionally, the direct stimulation techniques described
herein may be used to directly stimulate individual nerve ganglion of the
sympathetic nervous system, such as, for example, the celiac ganglion,
superior mesenteric ganglion, inferior mesenteric ganglion and others
listed in FIGS. 32, 33 or known to those of ordinary skill. It is to be
appreciated that the stimulation systems, pulse generators and
microelectrodes and other components are modified and sized as needed to
allow for direct stimulation of the ganglion including implanting into
the ganglion or within adjacent nerve sheaths leading to the ganglion.
FIG. 34 illustrates the combined direct stimulation of a DRG 38 with
microelectrode 115 as well as a suitable sized microelectrode 115
implanted in a sympathetic nerve root ganglion 63. The electrodes in FIG.
34 may stimulated independently or in a coordinated fashion to achieve
the desired clinical outcome or other desired result. Similar to the
discussion above for electrode placement in the DRG, electrode placement
for the sympathetic chain may also be unilateral, bilateral, on adjacent
portions of the chain or separate portions of the chain as needed.

[0182] One aspect of the present invention is a method of modulating a
neural pathway in the sympathetic nervous system including stimulating a
spinal dorsal root ganglion upstream of at least one ganglion of the
sympathetic nerve chain to influence a condition associated with the at
least one ganglion of the sympathetic nerve chain. In one specific
embodiment, stimulating a spinal dorsal root ganglion comprises
stimulating a spinal dorsal root ganglion upstream of at least one
ganglion of the sympathetic nerve chain to influence functional
activation of a bodily system associated with the at least one ganglion
along the sympathetic nerve chain, to influence functional activation of
an organ associated with the at least one ganglion along the sympathetic
nerve chain, or to influence functional inhibition of a bodily system
associated with the at least one ganglion along the sympathetic nerve
chain. In specific embodiments, the ganglion of the sympathetic nerve
chain is a cervical ganglion, a thoracic ganglion, or a lumbar ganglion.

[0183] In another aspect, the method of modulating a neural pathway in the
sympathetic nervous system includes application of stimulation using an
electrode exposed to the spinal dorsal root ganglion epinurium. In
another aspect, the application of stimulation is performed using an
electrode within the dorsal root ganglion. Alternatively, or in addition,
stimulation may be applied to at least one ganglion along the sympathetic
nerve chain using an electrode exposed to the at least one ganglion or
using an electrode implanted within the at least one ganglion or applying
stimulation along the sympathetic nerve chain.

[0184] FIGS. 35, 36 and 38 illustrate how embodiments of the stimulation
system, methods and microelectrodes described herein may be
advantageously employed for direct stimulation of the spinal cord. Those
of ordinary skill will appreciate that a pulse generator, battery and
other stimulation system components described above would be used to
drive the spinal electrodes described herein. As illustrated in FIG. 35,
a microelectrode 115 has been advanced through the epidural space 26
through the dura matter 32 and into the spinal cord 13. In the
illustrated embodiment the electrode 13 is positioned in the spinal cord
13 with an anchor 124 in the vertebral body 70 along with a strain
reducing element 122 (i.e., a coil of microelectrode lead 110). FIG. 36
illustrates two electrodes implanted into the spinal cord 13 for direct
stimulation. Optionally or additionally, anchors and seals may also be
provided and are further described below with regard to FIGS. 37A, B and
C. While the illustrative embodiments show an electrode implanted at a
depth into the spinal cord, electrodes may be surface mounted as well.
For example, electrodes may be placed in positions that just pierce the
outer surface up to a depth of 1 mm or alternatively at depths from 2 mm
to 12 mm or as otherwise needed to accomplish the desired stimulation
therapy or treatment.

[0185] Embodiments of the present invention provide a method of
stimulating the spinal cord that includes implanting an electrode into
the spinal cord and providing stimulation energy to spinal cord fibers
using the electrode. In one aspect, the stimulation energy is provided to
the spinal cord using the electrodes at a level below the energy level
that will ablate or otherwise damage spinal cord fiber. In specific
embodiments, the spinal microelectrode is implanted into the cuneate
fascicle, the gracile fascicle, the corticospinal tract, an ascending
neural pathway, and/or a descending neural pathway.

[0186] In another specific embodiment, a method for stimulation of the
spinal cord includes piercing the spinal dura matter and placing an
electrode into contact with a portion of the intra-madullary of the
spinal cord. Additionally, the portion of the intra-madullary of the
spinal cord may include the cuneate fascicle, the gracile fascicle, the
corticospinal tract. Additionally or optionally, the electrode may be
implanted into the portion of the intra-madullary of the spinal cord
including a portion of the intra-madullary that controls pain from the
upper extremities, the lower extremities, an upper spinal cord pain
pathway, or a lower spinal cord pain pathway. Additionally or optionally,
an electrode may be implanted into and directly stimulate a portion of
the intra-madullary of the spinal cord that influences control of an
organ, such as for example, autonomic bladder stimulation, or other body
function.

[0187] FIGS. 37A-37C illustrate alternatives to sealing the spinal dura 32
after the dura is pierced during the electrode implantation procedure. In
one aspect, the present invention provides methods of forming an opening
in the spinal dura, passing the electrode through the opening in the
spinal dura and sealing the opening in the spinal dura 32. Additionally,
atraumatic anchors 3717 may also be provided distal to the electrode 3715
to assist with maintaining electrode position in the spinal cord 13 after
implantation, as well as resist pull out. The anchors 3717 may be formed
from any suitable biocompatible material that is flexible and will not
contaminate the surrounding cerebral spinal fluid. In FIG. 37A, a single
fibrous seal 3710 is disposed distal to the anchor 3717 against the
interior wall of the dura 32. Examples of suitable seal materials for
seals 3710, 3720 and 3725 include, for example, tissue glue, synthetic
fibers, gel foam, hydrogels, hydrophilic polymers or other materials
having fabric characteristics suited to sealing. Each of the seals
described herein may be separate from or integrally formed with an anchor
3717. FIG. 37B illustrates an embodiment where a seal 3720 is provided on
the exterior wall of the dura 32. FIG. 37c illustrates the use of two
seals. A seal 3725 against the inner dura wall and a seal 3720 against
the outer dura wall. Examples of suitable seal materials for seals 3720,
3725 include: vascular suture pads, polyurethane, fluorinated polymers,
biodegradable polymers such as PLA/PGLA. Seals as described herein are
adapted to prevent CSF leakage through the hole in the dura formed during
electrode implantation. In alternative embodiments, the component passing
through the dura after implantation (either a microelectrode shaft or
microelectrode leads depending upon design) has a material or surface
that engages with the seal 3717, 3720 and assists in sealing the dura. In
one specific embodiment, the seal 3720 could be a fabric pad such as a
vascular suture pad and the seal 3725 could be a polymer or a form of
tissue glue.

[0188]FIG. 38 illustrates and summarizes numerous specific targets for
stimulation and electrode placement within the nervous system. Nerves on
only one side of the spinal cord are shown. FIG. 38 illustrates several
alternative microelectrode placement locations depending upon desired
stimulation, neural response or treatment of a condition. Embodiments of
the present invention employ appropriately small sized microelectrodes
thereby enabling the selective stimulation of numerous specific portions
of the nervous system in addition to the specific embodiments described
herein. Microelectrodes are illustrated in the DRG dura (1), within the
DRG through the dura (2A), within the DRG by traversing the peripheral
nerve sheath (2B). The spinal cord may be stimulated by implanting
electrode(s) into ascending pathways 92, descending pathways 94 or fibers
96. Spinal cord stimulation may also be accomplished by placing
microelectrodes into specific spinal cord regions such as the cuneate
fascicle 3, gracile fascicle 4 or the corticospinal tract 5.
Additionally, electrodes may be placed in the spinal cord near the root
entry into the cord, such as dorsal root 42H and ventral root 41H.
Embodiments of the present invention also enable microelectrode placement
and direct stimulation can be advantageously positioned and applied so as
to influence and/or control bodily function(s).

[0189] In some embodiments, direct stimulation refers to the application
of stimulation or modulation energy to neural tissue by placing one or
more electrodes into contact with the targeted neural tissue. In some
specific embodiments, contact with the targeted neural tissue refers to
electrode placement on or in a nerve ganglion. In other embodiments, one
or more electrodes may be placed adjacent to one or more nerve ganglion
without contacting the nerve ganglion. Electrode placement without
contacting the nerve ganglion refers to positioning an electrode to
stimulate preferentially only a nerve ganglion. Stimulation of
preferentially only a nerve ganglion refers to electrode placement or
electrode energy delivery to targeted neural tissue without passing the
neurostimulation or modulation energy through an intervening
physiological structure or tissue.

[0190] Several advantages of the inventive stimulation system and methods
described herein are made clear through contrast to existing conventional
stimulation systems such as those described in, for example, U.S. Pat.
No. 6,259,952; U.S. Pat. No. 6,319,241 and U.S. Pat. No. 6,871,099 each
of which are incorporated herein by reference.

[0191] Consider for example a conventional stimulation electrode placed
within a vertebral body for stimulation of a dorsal root ganglion. A
portion of the stimulation energy provided by an electrode so positioned
will be attenuated or absorbed by the surrounding bone structure. As a
result, the initial stimulation energy provided in this system must be
large enough to compensate for propagation losses through the bone while
still having sufficient remaining energy to accomplish the desired
stimulation level at the dorsal root ganglion. The stimulation energy of
this conventional system will also be non-specifically applied to the
intervening physiological structures such as the spinal cord, peripheral
nerves, dorsal root, ventral root and surrounding tissue, cartilage and
muscle. Each of these intervening physiological structures will be
subjected to the stimulation energy and may cause undesired consequences.
In addition, each of these physiological structures will be subjected to
and may attenuate or absorb the stimulation energy before the energy
reaches the desired neural tissue.

[0192] Consider the additional examples of conventional stimulation
electrodes placed (a) within the dorsal root between the spinal dura and
the spinal cord and (b) within the peripheral nerve. Neurostimulation of
a dorsal root ganglion from these positions is complicated by ways
similar to the above example. The stimulation energy provided by the
electrode must pass through or may be absorbed by numerous surrounding
physiological structures. A portion of the stimulation energy provided by
an electrode in position (a) will be attenuated or absorbed by, for
example, the surrounding dorsal root sheath, cerebral spinal fluid and
the spinal cord. The stimulation energy provided in this system must be
large enough to compensate for propagation losses through the dorsal root
sheath, cerebral spinal fluid and protective spinal cord layers (i.e.,
the spinal meninges: pia mater, arachnoid mater and dura mater) while
still having sufficient remaining energy to accomplish the desired
stimulation level in the dorsal root ganglion. The stimulation energy
will also be non-specifically applied to the spinal cord. A portion of
the stimulation energy provided by an electrode in position (b) will be
attenuated or absorbed by, for example, the peripheral nerve bundles
including motor nerve bundles. The stimulation energy provided in this
system must be large enough to compensate for propagation losses through
the peripheral nerve while still having sufficient remaining energy to
accomplish the desired stimulation level in the dorsal root ganglion.
Unlike the present invention, the stimulation energy provided by
electrode placement (b) will also apply stimulation energy to the motor
nerves within the peripheral nerve. Electrode placement in positions (a)
and (b) above each have intervening physiological structures that are
subjected to the stimulation energy and may cause undesired consequences.
In addition, each of the intervening physiological structures will be
subjected to and may attenuate or absorb the stimulation energy before
the energy reaches the desired neural tissue.

[0193] Embodiments of the present invention provide stimulation energy via
one or more electrodes placed on, in or in proximity to the targeted
neural tissue. The intimate nature of the electrode placement allows
substantially less stimulation energy to be used to achieve a comparable
neurostimulation level. One reason it is believed that that lower power
levels may be used in the inventive techniques is that the lack of
attenuation losses caused by subjecting intervening physiological
structures to stimulation energy. Conventional systems remain concerned
about the generation of heat and the possibility of heat induced tissue
damage because conventional stimulation systems subject intervening
tissues and targeted tissues to stimulation energy. Many conventional
stimulation systems are provided with or utilize tissue temperature for
control or feedback. Tissue temperature is a useful parameter for these
conventional systems because they provide sufficient energy to
substantially or measurably raise the temperature of the surrounding
tissue or intervening structures. These conventional stimulation systems
raise the temperature of surrounding tissue by tens of degrees Celsius
while maintaining temperatures below the average temperature range that
is thermally lethal such as that used by heat lesioning procedures (i.e.,
below 45 C).

[0194] In contrast to systems that raise the temperature of both targeted
and surrounding tissue, it is believed that the stimulation energy levels
provided by embodiments of the present invention are low enough that the
temperature of the targeted neural tissue does not increase a measurable
amount or less than one degree Celsius. The stimulation levels provided
by some embodiments of the present invention are within or below (a) the
milliwatt range; (b) the millijoule range and/or (c) the microjoule
range. It is also believed that the stimulation levels provided by some
embodiments of the present invention are sufficiently low that the
temperature of tissue surrounding an electrode is unaffected, increases
by less than 5 degrees C., or less than 1 degree C. Moreover, it is
believed that the stimulation energy levels provided by other embodiments
of the present invention are low enough that the temperature of the
surrounding tissue and other physiological structures is below a
measurable amount using conventional temperature measurement techniques
or below one degree Celsius. It is to be appreciated that the stimulation
energy levels provided by embodiments of the present invention are
substantially below those conventional stimulation systems that
measurably elevate the temperature of surrounding tissue or operate at
levels approaching the level of thermal ablation and lesioning.

[0195] It is to be appreciated that embodiments of the specific
stimulation techniques of the present invention may be utilized alone to
achieve the described stimulation techniques or in a combined upstream or
downstream configurations with the described stimulation techniques and
systems described in the following references (each of which is
incorporated herein in its entirety): U.S. Pat. No. 5,948,007 to
Starkebaum; U.S. Pat. No. 5,417,719 to Hull; U.S. Pat. No. 6,658,302 to
Kuzma; U.S. Pat. No. 6,606,521 to Paspa; and U.S. Pat. No. 5,938,690 to
Law.

[0196] It may be appreciated that the neuromodulation provided to the
patient is typically maintained throughout the treatment of the patient's
condition. When such treatment is for a chronic condition, the electrodes
continue to provide neuromodulation of the target anatomy, such as the
dorsal root ganglion, over long periods of time and maintain a
comfortable paresthesia sensation for the patient. Typically, paresthesia
is provided in a distribution over the affected body region and is
maintained at a desired intensity throughout the patient's daily
activities. As mentioned above, in some embodiments, the stimulation
energy is modified based on activity level to provide desired paresthesia
during varying activities. In other embodiments, paresthesia is
maintained during varying activities to provide a continuous level of
intensity and/or distribution. This may particularly be the case when a
patient changes body position between an upright position, such as
standing up, and a recombinant position, such as lying face-up or
face-down. Other changes in body position include, for example, flexion,
extension or rotation of a portion of the spine. With such changes in
body position, it is often desired to maintain paresthesia levels and
distribution to avoid sudden undesired surges of stimulation or other
uncomfortable sensations.

[0197] In some embodiments, at least one electrode is implanted in
proximity to a target tissue, such as a dorsal root ganglion, so that the
at least one electrode maintains position in proximity to the target
tissue throughout a body position change of the patient. Such maintenance
of position holds the electrode in relation to the target tissue so that
the electrode does not move closer or further from the target which would
alter the stimulation effects. For example, movement of the electrode
closer to the target would suddenly increase stimulation. Thus, sudden
surges or stimulation are avoided or reduced. Maintaining position of the
at least one electrode maintains intensity of paresthesia, distribution
of paresthesia, or both.

[0198] In some embodiments, maintenance of position is achieved with the
use of an anchor. A variety of example anchors and anchoring techniques
have been described herein, such as attaching to adjacent bony structure,
soft tissue or other neighboring anatomical structures. Likewise, a
fixation, anchoring or bonding structure has been described, positioned
proximal to an electrode anchor that absorbs some or all proximal
movement of the leads so that the electrode is less likely to be pulled
from or dislodged from the implantation site. The goal of the anchoring
and other strain absorbing features is to ensure the electrode remains in
place within or is less likely to migrate from the implanted position
because of electrode lead movement. It is to be appreciated that numerous
techniques are available to aid in electrode placement including
percutaneous placement of single/multiple hooks or anchors, vertebral
anchor or posts, micro-sutures, cements, bonds and other joining or
anchoring techniques known to those of ordinary skill in the art. In
other embodiments, lack of clinically significant changes in paresthesia
during movement of the patient is achieved without use of an anchor. Due
to the anatomical features surrounding the dorsal root ganglion,
implantation of an electrode in proximity to a dorsal root ganglion can
maintain position of the electrode during body movements, such as
movements of portions of the spine or changes in body position. In
particular, when an electrode is positioned adjacent to a surface of the
dorsal root ganglion, such as within a foramen, minimal cerebral spinal
fluid is disposed between the electrode and the dorsal root ganglion.
Typically, fluctuations in cerebral spinal fluid depth cause increases
and decreases in the distance between the electrode and the target tissue
during body movements. However, since cerebral spinal fluid is minimized
in the area of the dorsal root ganglion, such fluctuations do not occur
or are so minimal as to avoid clinically significant effects in
stimulation and therefore paresthesia intensity and/or distribution.

[0199] To verify the maintenance of paresthesia intensity and distribution
during body movements, various studies have been undertaken. To begin,
patients having at least one electrode implanted near a dorsal root
ganglion were provided stimulation energy at known levels. Referring to
FIGS. 39A-39B, the patient rated the intensity of the paresthesia at each
energy level during various body positions. FIG. 39A illustrates an 11
point scale 300 in which a patient rates the paresthesia intensity while
standing up at a particular stimulation level. FIG. 39B illustrates an 11
point scale 302 in which a patient rates the paresthesia intensity while
lying down at the same stimulation level. In both instances, a rating of
"0" indicated no feeling of paresthesia while a rating of "10" indicated
a very intense feeling of paresthesia. FIG. 40 is an example of data
compiled for a given patient comparing stimulation level (current
amplitude) and paresthesia intensity while the patient is in a particular
body position. As shown, as the current amplitude was increased, the
intensity of paresthesia sensed by the patient increased in a
corresponding manner. In this example, the coefficient of determination
is 0.9812 which indicates that the data is highly linear. Thus, it may be
assumed that if a patient senses an increase in paresthesia intensity
during normal body movements, such a change in paresthesia intensity
correlates directly to a change in stimulation. When the stimulation
parameters are held constant, such a change would be due to movement of
the electrode in relation to the target, however slight.

[0200]FIG. 41 is a bar graph illustrating complied paresthesia intensity
data from 22 patients. The first bar 350 indicates a paresthesia
intensity value of 5.3 on the 11 point scale 300 when the patient is in
an upright position and stimulation is at a given level. The second bar
352 indicates a paresthesia intensity value of 5.6 on the 11 point scale
302 when the patient is in a supine position and stimulation is at the
same given level. The difference in paresthesia intensity values (5.3 vs.
5.6) is not clinically significant and indicates that paresthesia is
maintained throughout these body position changes.

[0201]FIG. 42 is a line graph illustrating the maintenance of paresthesia
intensity over time. At each time point, a cohort of patients rated
paresthesia intensity on the 11 point scale 300 while in an upright
position and paresthesia intensity on the 11 point scale 302 while in a
supine position. Time points included after placement and programming of
a temporary neurostimulator ("Post-TNS Programming"), at the end of the
trial period with the temporary neurostimulator ("End of TNS"), after
placement and programming of a permanent implantable neurostimulator
("Post-INS Programming"), and at 1 week, 4 weeks, 8 weeks, 3 months, 6
months, and 12 months after implantation of the permanent implantable
neurostimulator. Line 350 indicates paresthesia intensity values over
time for patients while in an upright position and line 352 indicates
paresthesia intensity values over time for patients while in a supine
position. The difference in paresthesia intensity values is not
clinically significant and indicates that paresthesia intensity is
maintained throughout these body position changes and is consistent over
time.

[0202] FIGS. 43A-43B are body maps illustrating paresthesia distribution.
In this example, the patient has an electrode implanted near a dorsal
root ganglion. FIG. 43A illustrates areas on the patient body P where
paresthesia is felt while the patient is in an upright position. Areas of
paresthesia are indicated by shading 400. FIG. 43B illustrates areas on
the patient body P where paresthesia is felt while the patient is in a
supine position. Areas of paresthesia are indicated by shading 402. The
difference in paresthesia distribution is not clinically significant and
indicates that paresthesia distribution is maintained throughout these
body position changes.

[0203] While preferred embodiments of the present invention have been
shown and described herein, it will be obvious to those skilled in the
art that such embodiments are provided by way of example only. Numerous
variations, changes, and substitutions will now occur to those skilled in
the art without departing from the invention. It should be understood
that various alternatives to the embodiments of the invention described
herein may be employed in practicing the invention. It is intended that
the following claims define the scope of the invention and that methods
and structures within the scope of these claims and their equivalents be
covered thereby.